Secretory phospholipase A2 of group IIA: Is it an offensive or a defensive player during atherosclerosis and other inflammatory diseases?

Prostaglandins & other Lipid Mediators 79 (2006) 1–33

Review

Secretory phospholipase A2 of group IIA: Is it an offensive or a defensive player during atherosclerosis and other inflammatory diseases? Mario Menschikowski ∗ , Albert Hagelgans, Gabriele Siegert Technische Universit¨at Dresden, Medizinische Fakult¨at “Carl Gustav Carus”, Institut f¨ur Klinische Chemie and Laboratoriumsmedizin, Fetscherstrasse 74, D-01307 Dresden, Germany Received 18 July 2005; received in revised form 29 October 2005; accepted 31 October 2005 Available online 27 December 2005

Summary Since its discovery in the serum of patients with severe inflammation and in rheumatoid arthritic fluids, the secretory phospholipase A2 of group IIA (sPLA2 -IIA) has been chiefly considered as a proinflammatory enzyme, the result of which has been very intense interest in selective inhibitors of sPLA2 -IIA in the hope of developing new and efficient therapies for inflammatory diseases. The recent discovery of the antibacterial properties of sPLA2 -IIA, however, has raised the question of whether the upregulation of sPLA2 -IIA during inflammation is to be considered uniformly negative and the hindrance of sPLA2 -IIA in every instance beneficial. The aim of this review is for this reason, along with the results of various investigations which argue for the proinflammatory and proatherogenic effects of an upregulation of sPLA2 -IIA, also to array data alongside which point to a protective function of sPLA2 IIA during inflammation. Thus, it could be shown that sPLA2 -IIA, apart from the bactericidal effects, possesses also antithrombotic properties and indeed plays a possible role in the resolution of inflammation and the accelerated clearance of oxidatively modified lipoproteins during inflammation via the liver and adrenals. Based on these multipotent properties the knowledge of the function of sPLA2 -IIA during inflammation is a fundamental prerequisite for the development and establishment of new therapeutic strategies to prevent and treat severe inflammatory diseases up to and including sepsis. © 2005 Elsevier Inc. All rights reserved. Keywords: Secretory phospholipase A2 ; Inflammation; Atherosclerosis; Sepsis; Statins; HMG-CoA reductase inhibitors

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Distribution and induction of sPLA2 -IIA expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 3

Abbreviations: C/EBP-␤, CAAT-enhancer-binding protein-␤; cPLA2 , cytosolic phospholipase A2 ; ERK, extracellular signal-regulated kinase; FPP, farnesyl pyrophosphate; FTI, farnesyl transferase inhibitor; GGPP, geranylgeranyl pyrophosphate; GGTI, geranylgeranyl transferase-I inhibitor; HASMC, human aortic smooth muscle cells; HDL, high-density lipoproteins; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; IFN-␥, interferon-␥; IL-1␤, interleukin-1␤; IL-6, interleukin-6; Jak, Janus kinase; LDL, low-density lipoproteins; MEK, mitogen-activated/extracellular response protein kinase kinase; NF-␬B, nuclear factor-kB; PLA1 , phospholipases A1 ; PLA2 , phospholipases A2 ; PLB, phospholipases B; PLC, phospholipases C; PLD, phospholipases D; sPLA2 -IIA, secretory phospholipase A2 of type IIA; STAT, signal transducer and activator of transcription; TNF-␣, tumor necrosis factor-␣; VCAM-1, vascular cell adesion molecule-1; VSMC, vascular smooth muscle cells ∗ Corresponding author. Tel.: +49 351 458 2634; fax: +49 351 458 4332. E-mail address: [email protected] (M. Menschikowski). 1098-8823/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.prostaglandins.2005.10.005

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3. 4.

5.

6.

Proinflammatory effects after local application of sPLA2 -IIA in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Data suggesting a proatherogenic role of sPLA2 -IIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Identification of sPLA2 -IIA expression in atherosclerotic lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Possible proatherogenic effects of sPLA2 -IIA upregulation in the vessel wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Substrate specificities of sPLA2 -IIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. General enzymatic properties of sPLA2 s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Low substrate specificity of sPLA2 -IIA to native lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3. Failed substrate specificity of exogenously added sPLA2 -IIA to normal cell membranes . . . . . . . . . . . . . 4.3.4. Increased susceptibility of oxidatively modified lipoproteins to sPLA2 -IIA . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.5. Increased susceptibility of injured and apoptotic cell membranes to sPLA2 -IIA . . . . . . . . . . . . . . . . . . . . . 4.4. In vivo data indicating a role of sPLA2 -IIA in the lipoprotein metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Increased susceptibility of sPLA2 -IIA-transgenic mice to atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Data suggesting alternative functions of sPLA2 -IIA during inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Bactericidal properties of secretory phospholipases A2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Antithrombotic properties of sPLA2 -IIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Enhanced clearance of oxidative modified lipoproteins during inflammation by sPLA2 -IIA via liver and adrenals 5.4. In vitro data suggesting antiapoptotic properties of sPLA2 -IIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. In vivo and in vitro data suggesting antiinflammatory properties of sPLA2 -IIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 6 6 7 8 8 9 10 12 12 12 14 15 15 17 18 18 19 20 21

1. Introduction Phospholipases are classified as esterases and ubiquitous in mammal organisms. Corresponding to the positions of the ester bonds, which are split hydrolytically by the phospholipases, the enzymes can be distinguished as the acylhydrolases PLA1 , PLA2 , PLB and lysophospholipases as well as the phosphodiesterases PLC and PLD [1]. Membrane phospholipids of mammalian cells are especially rich in polyunsaturated fatty acids such as arachidonic acid, which is mainly bound in the sn-2-position of phospholipids. Arachidonic acid in turn functions as a substrate in the cyclooxygenase- and lipoxygenase-mediated biosynthesis of eicosanoids, including prostaglandins, leukotrienes, thromboxanes and prostacyclins, which exist as short-lived and biologically active signal molecules. Furthermore, along with the free fatty acids in the PLA2 -promoted reaction, lysophospholipids such as lysophosphatidic acid, lysophosphatidylcholine and lysophosphatidylethanolamine are produced, which exhibit cytolytic, chemotactic and mitogenic properties and are precursors of other bioactive mediators such as the platelet-activating factor (PAF) [2,3]. These numerous proinflammatory lipid mediators and the fact that cellularly only small concentrations of free arachidonic acid are present, make the role of PLA2 in inflammations more meaningful since the rate-limiting step in the generation of arachidonic acid is controlled by these enzymes. Alternatively, arachidonic acid is also liberated from cellular phospholipids through the combined activity of PLC and diacylglycerol lipase or PLA1 and PLB [1]. During the past decade, a great number of new PLA2 s have been discovered expanding the superfamily of PLA2 to at least 20 different enzymes. To date, there are four major families of PLA2 : secretory PLA2 s (sPLA2 of groups I, II, III, V, X and XII), cytosolic PLA2 s (cPLA2 or PLA2 s of group IV), calcium-independent PLA2 s (iPLA2 or PLA2 s of group VI) and PAF acetylhydrolyses (PAF-AH or PLA2 s of groups VII and VIII) (reviewed in Refs. [4–6]). Among them, sPLA2 s exist in at least 10 different mouse enzymes (groups IB, IIA, IIC, IID, IIE, IIF, III, V, X and XII) and at least 9 are present in human (with the exception of IIC, which occurs as a pseudogene [5,6]). Although the sPLA2 s of group I, II, V and X are closely related and have very similar catalytic sites, evidence is emerging that these enzymes display very different interfacial binding properties. One of the best-characterized types of the structurally heterogeneous superfamily of PLA2 enzymes is the secretory phospholipase A2 of group IIA (sPLA2 -IIA) [7,8], which was initially isolated from rheumatoid arthritic synovial fluid and platelets and which was originally designated as non-pancreatic or synovial-specific PLA2 [9–11]. Large amounts of this enzyme have been found at various inflamed sites and in the serum of patients with severe inflammations such as sepsis, septic shock and polytrauma. The level of enzyme expression correlated strongly with the degree of the disorders [12–15]. These data suggest that sPLA2 -IIA plays a pivotal role in inflammation. Furthermore, it has been shown in animal inflammation models that sPLA2 -IIA acts to promote inflammation (for review Ref. [16]). Based on

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these findings there exists some considerable hope that with the help of specific inhibitors of sPLA2 -IIA new forms of therapy for severe inflammatory diseases can be established. The specific biological functions of sPLA2 -IIA, however, are not completely understood. In addition to cell injury, sPLA2 -IIA may be involved, similar to other phospholipases A2 , in cell signaling, apoptosis and remodelling of cell membranes [4–6]. Beyond this, new in vivo investigations have shown that in sPLA2 -IIA an efficient bactericidal agent is available [17–25]. Because of this the question arises as to how far a suppression of sPLA2 -IIA, especially in bacterially caused inflammatory diseases, can be considered really beneficial in each stadium of the disease’s progression. This question also arose because of data from a recently published clinical trail applying a selective inhibitor of sPLA2 -IIA, LY315920NA/S-5920 [26]. In this study the inhibition of the enzyme not only failed to improve the clinical outcome for patients with severe sepsis, but also revealed a negative trend in the 28-day-all-cause mortality. Furthermore, recent in vitro studies have concluded that statins lead to a potentiation of the IFN-␥-mediated sPLA2 -IIA induction in HASMC and HepG2 cells [27] instead of a reduction, as we had at first assumed based on the published antiinflammatory properties of statins [28–30]. Similar effects of statins in IL-1␤-stimulated rat mesangial cells have been described by Petry et al. [31]. Given the assumption that sPLA2 -IIA acts proinflammatory and proatherogenic, as described later in more detail, this effect stands in contradiction of the benefit of statins in primary and secondary prevention of coronary heart diseases [32–35]. One simple explanation could be that the presumed proinflammatory and proatherogenic effects of sPLA2 -IIA upregulation are negligible because of the other cardioprotective effects of statins such as inhibition of cholesterol biosynthesis or increased synthesis of nitric oxide [36–38]. On the other hand, it is known that activation of sPLA2 -IIA produces multiple but controverting effects in different tissues [39]. There is evidence, for example, that sPLA2 -IIA, in addition to its bactericidal properties, exhibits also antithrombotic and antiinflammatory properties as well, from which it could be concluded that sPLA2 -IIA expression, with its pathogenic effects, is indeed associated with protective functions, which will be treated more closely hereunder. 2. Distribution and induction of sPLA2 -IIA expression Mammalian sPLA2 -IIA is constitutively expressed in a number of different cells, such as platelets [40], neutrophils, macrophages and mast cells, in which the enzyme is stored in secretory granules [41–43], and in tissues such as prostate [44], placenta [45], spleen, small intestinal mucosa, tonsil, parotid and lacrimal glands, cartilage and bone marrow [16,44] as well as in body fluids such as seminal plasma [46,47] and tears [48]. In the prostate especially glandular epithelial cells are immunohistochemically positive for sPLA2 -IIA. Based on these findings it is supposed that sPLA2 IIA, which occurs in seminal fluid, actually has its origin in the prostate. The function of sPLA2 -IIA in seminal fluid and in the prostate is still unknown. In an early study, the sPLA2 activity in seminal plasma has been connected with an active prostaglandin biosynthesis [49], however, further investigations are necessary. Moreover, fusogenic properties of lysophospholipids, that are released in the sPLA2 -IIA-catalysed reaction, have been described, which may improve the sperm penetration through the egg plasma membrane [50]. The bactericidal properties of sPLA2 -IIA can also be meaningful in seminal fluid. Furthermore, sPLA2 -IIA has been identified in intestinal Paneth-cells [51,52] where it can also be involved in the immune host response system. Because inhibitors of sPLA2 blocked the uptake of cholesterol [53] and sPLA2 -IB knockout mice at a chow diet did not show abnormalities in dietary lipid absorption, it has been suggested that other sPLA2 s can contribute to hydrolysis of dietary phospholipids and compensate for sPLA2 -IB [54]. Based on the fact that the analyzed sPLA2 -IB knockout mice were back-crossed into the C57BL/6 background connected with a knockout for sPLA2 -IIA [55], however, a compensation for sPLA2 -IB by sPLA2 -IIA can be excluded at least in this animal model. Finally, high concentrations of sPLA2 -IIA in the placenta can be found [56]. The function of the enzyme in this tissue is, however, as yet not particularly well explained, but it has been implicated in the release of arachidonic acid for eicosanoid synthesis [57]. The sPLA2 -IIA enzyme activity in the serum of healthy individuals is principally low. During an acute inflammatory disorder such as sepsis and septic shock [58–60], acute pancreatitis [61,62], peritonitis [62] or appendicitis [63], it can rise dramtically. In fact values of from 100 to 1000 times the norm have been observed in these illnesses. As with chronic rheumatoid arthritis [15,64] elevated blood serum values of sPLA2 -IIA in neoplastic are found [65–68]. Thus, in prostatic intraepithelial neoplasie and adenocarcinoma the expression of sPLA2 -IIA is elevated and correlates with the prostate tumor grade [67,68]. The function of sPLA2 -IIA during tumorgenesis, however, also remains still unresolved. On the basis of data obtained from Min mice carrying mutations in the adenomatous polyposis coli gene

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and which develop multiple adenomas throughout their small and large intestine, a protective function of sPLA2 -IIA has been suggested [69]. However, this assumption could not be proven in humans where sPLA2 -IIA gene mutations do not appear to play a major role in the development of colorectal cancers [70]. On the contrary, proongogenic properties of sPLA2 -IIA upregulation have been suggested from studies on different prostatic tumor cell-lines and a xenograft tumor model [71,72]. Nevertheless, it is unclear whether the sPLA2 -IIA upregulation in neoplastic tissues is causally related with the initiation and progression of the disease or whether it reflects the inflammatory activities in tumors. Further disorders associated with inflammatory processes where the sPLA2 -IIA seems to play an important role are ischemia [73,74] and neurodegenerative diseases including stroke and Alzheimer’s disease [75–77]. The origin of the serum group IIA PLA2 is still the subject of lively discussion. Numerous cells and tissues are under consideration as the location of synthesis. In this sense it has been found that in chondrocytes, endothelial cells, smooth muscle cells, renal mesangial cells and astrocytes an expression of the enzymes through incubation with bacterial lipopolysaccharide (LPS), interleukin-1␤ (IL-1␤), interleukin-6 (IL-6), tumor necrosis factor-␣ (TNF-␣), interferon␥ (IFN-␥) and cAMP-elevating agents in vitro can be induced [78–82]. Furthermore, Crowl et al. [83] established, that proinflammatory cytokines such as IL-1␤, IL-6 and TNF-␣ in human HepG2 hepatoma cells induce a synthesis and secretion of sPLA2 -IIA. Therefore, along with activated leukocytes and smooth muscle cells the liver is being discussed as the site of synthesis for the observed sPLA2 -IIA in serum and for the reason of the rapid rise during a local or systemic inflammatory reaction sPLA2 -IIA is counted with the acute-phase-reactants [84]. Along this line the level of serum PLA2 -IIA correlates with the concentration of the C-reactive protein in several acute and chronic diseases as well as in postoperative states [85–88]. The sPLA2 -IIA expression is regulated by different intracellular signaling cascades involving RhoA/Rho-associated kinase, Ras/MEK/ERK, p38 MAPK, PI3-K/Akt and glycogen synthase kinase (GSK)-3␤ in a cell-specific manner (Table 1). A negative control of sPLA2 -IIA synthesis and secretion by Rho/Rho-associated kinase pathway likely represents a common regulatory mechanism which is realized at least in HASMC and HepG2 [27] and in rat renal mesangial cells [31]. Contrary to that, inhibition of MEK/ERK pathway by PD-98059 causes opposite effects on sPLA2 -IIA expression; on the one hand, activation in HASMC and HepG2 hepatoma cells [27], on the other, inhibition in rat VSMC [89] and rat astrocytes [90]. At present the mechanism underlying the increased sPLA2 -IIA production by MEK/ERK inhibition in HASMC and HepG2 cells is unknown. It is interesting, however, that inhibition of MEK signaling by PD-98059 induced STAT3 activation in a dose-dependent manner in HepG2 cells [91], especially as it is known that STAT3 participates in IFN-␥ induced sPLA2 -IIA upregulation in HASMC [126]. The Jak/STAT pathway is a major and best-characterized IFN-␥ signaling pathway, which may synergistically interact with NF-␬B and C/EBP-␤ at the pretranscriptional and transcriptional level [92–94]. Furthermore, it has been shown that the expression of sPLA2 IIA in HASMC is also regulated at posttranscriptional level, as the inhibition of Ras- and Rho-dependent signaling by statins resulted in a prolongated half-life of sPLA2 -IIA-mRNA [27]. 3. Proinflammatory effects after local application of sPLA2 -IIA in vivo In order to identify the physiological and/or pathophysiological function of sPLA2 -IIA during inflammation, the effects after local application of purified or recombinant sPLA2 -IIA alone and by administering more or less specific sPLA2 -IIA-inhibitors in a variety of different animal models were investigated for review Ref. [16]. In rats, for example, the intra-articular injection of sPLA2 -IIA purified from human rheumatoid synovial fluid resulted in an acute inflammatory infiltrate of subsynovium, which did not occur after previous inactivation of the sPLA2 -IIA [95]. Similar proinflammatory effects were observed in rats after local injection of recombinant sPLA2 -IIA, which produced paw edema. Local treatment with anti-sPLA2 -IIA antibodies significantly reduced this edema formation [96]. In a further study of the same group it was found that the injection of sPLA2 -IIA in rat air pouch exacerbated the inflammatory response, but not if sPLA2 -IB or sPLA2 from Naja mocambique mocambique was injected [97]. Furthermore, a dramatic inflammatory response has been described when recombinant sPLA2 -IIA was injected into the joint space of healthy rabbits. Within 24 h extensive leukocyte infiltration and hyperplasia of the synovial lining cells occurred and increased prostaglandin production in the joint space was observed simultaneously [98]. However, an equivalent proinflammatory effect could not be established in all animal models after injection of sPLA2 -IIA. Whilst the injection of purified rat platelet phospholipase A2 into the hind paw of rats with adjuvant-induced arthritis resulted in exacerbation of edema in a dose-dependent manner, no effect was observed on either normal rats or animals with carrageenan-induced edema under the same experimental conditions [99]. In another study, the lack of paw edema-inducing activity of human

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Table 1 Regulation of sPLA2 -IIA expression by different signaling cascades and transcription factors Cell type

Group IIA secretory phospholipase A2 expression

References

Inductor

Positive modulation

Rat vascular SMC

IL-1␤, forskolin, oxysterols

NF-␬B, C/EBP-␤ and -␦, Ets, CBP/P300, Ras/MEK/ERK, cAMP/PKA, PPAR-␥, cPLA2 pathway cAMP/PKA

Glucocorticoid signaling

Human aortic SMC

IFN-␥ IFN-␥

STAT3 NF-␬B, C/EBP-␤, Jak2/STAT1␣, cAMP/PKA

RhoA/Rho-kinase, Ras/MEK/ERK, GSK-3␤

Rat cardiomyocytes

IL-1␤

p38 MAPK /MAPKAP-K2 -signaling

Alveolar macrophages

LPS/TNF-␣

NF-␬B

cAMP/PKA, AA, prostaglandins, PPAR-␥-signaling

[367,368]

Rat renal mesangial cells

IL-1␤, TNF-␣, forskolin

RhoA/Rho-kinase, PKC-␧, PDGF-BB-, bEGF-signaling, heparinase-1. Antioxidants

[31,212,369–371]

IL-1␤, TNF-␣, LPS

Negative modulation [89,361–363]

[125,364] [126] [27,365] [366]

TNF-␣

NF-␬B, PPAR-␣, cAMP/PKA, sPLA2 -IIA/cPLA2 cascade, iNOS pathway SMase/ROS/NF-␬B signaling

Human articular chondrocytes

8-Br-cAMP

No cytokine response

Rabbit articular chondrocytes

IL-1␤

TNF-␣

IGF-I-signaling

[373,374]

Rat calvarial osteoblastic cells

IL-1␤/TNF-␣, cAMP analoge

Microtubular system

TGF-␤-, PDGF-BB-, EGF-, bFGF-signaling

[375,376]

Human neuroblastoma cell line LAN-5

IFN-␥

G-proteins-signaling

Rat astrocytes

LPS, TNF-␣, IL-1␤

cAMP/PKA (+TNF-␣) PKC (+LPS)

DITNC cell line

TNF-␣ + IL-1␤ + IFN-␥

NF-␬B, tyrosine kinase-, and PAF-signaling NF-␬B, Ras/MEK/ERK, PI-3K/Akt, p38 MAPK

TNF-␣ Mouse epidermal keratinocytes

TPA, Ca2+ ionophore, bradykinin

PKC, cPLA2 activity

HepG2 hepatoma cells

IL-6, IL-1␤ TNF-␣ Oncostatin M

IL-6-responsive element cAMP/PKA C/EBP-␤, -␣ and -␦

IL-1␤, IL-6, IFN-␥, TNF-␣

NF-␬B, cAMP/PKA

[372] [373]

[377] Glucocorticoids signaling

[79] [378,379]

Thyroid hormones and growth factor signaling

[90] [380]

Glucocorticoids signaling Single strand DNA binding proteins (SSBP) RhoA/Rho-kinase, Ras/MEK/ERK, GSK-3␤

[83] [381,382] [383] [27,365]

recombinant sPLA2 -IIA has been described after a bolus subplantar injection, whereas a paw edema-inducing, acute inflammatory activity was found after snake venom phospholipase A2 (Naja naja naja, Naja mocambique mocambique and Crotalus atrox) injections [100]. To be able to investigate selectively the effect of an endogenously synthesized sPLA2 -IIA in vivo, i.e., without causing a concomitant increase of proinflammatory cytokines along with the induction of the enzyme, sPLA2 -IIA-transgenic mice were generated [101–103]. Surprisingly, except for an abnormality of the skin characterized by epidermal and adnexal hyperplasia, hyperkeratosis and nearly total alopecia, the sPLA2 -IIA-transgenic mice showed a normal phenotype, and despite the high enzyme activities in plasma and most organs, no signs of an inflammatory response have been

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detected in the skin or other tissues [101–103]. On the other hand, sPLA2 -IIA-transgenic mice were found to be more susceptible to LPS-induced septic shock in comparison to non-transgenic littermates, and TNF-␣+/+ /sPLA2 -IIA+/+ double transgenic mice developed more severe arthritis than mice expressing TNF-␣ alone [104]. Thus, it is conceivable that although sPLA2 -IIA alone was unable to induce inflammatory reactions, it may amplify an inflammatory response by contributing to the release of arachidonic acid from injured or apoptotic cell membranes, which will be discussed more closely below. Although the results of the in vivo-investigations are not consistent with one another, several of them support the conclusion that sPLA2 -IIA plays a crucial role in inflammation and that for this reason the inhibition of enzyme activity in the treatment of acute and chronic inflammatory disorders should be associated with a benefit. 4. Data suggesting a proatherogenic role of sPLA2 -IIA 4.1. Identification of sPLA2 -IIA expression in atherosclerotic lesions More than 180 years ago Rayer [105] stated the hypothesis of a possible connection between atherosclerosis and inflammation, which was later more closely investigated by Virchow [106]. More recently the availability of cell-specific monoclonal antibodies made possible several new conclusions about the molecular and subcellular composition of atherosclerotic lesions, which underlined that in atherosclerosis in fact numerous, for inflammations typical pathological occurrences can be demonstrated. These processes include in particular the augmented adhesion and infiltration of leukocytes, increased endothelial permeability for blood macromolecules, mesenchymal cell proliferation, activation of immunological processes, fibrosis, calcification and angiogenesis as well as enhanced platelet aggregation in the healing of wounds. Based on these observations Ross and Glomset [107,108] advanced the “response to injury”hypothesis, which says that atherosclerosis is a chronic inflammatory-fibroproliferative process in the arterial wall, which is at first induced as the protective response to certain toxins and pathophysiological changes. Depending on the type and length of the “stimulus”, the reactions can, however, become excessive and with the occurrence over years of the causative stimulants eventually lead to damage to the arterial wall. In the years following the hypothesis that atherosclerosis has much in common with chronic inflammatory reactions in other tissues was taken up again and again [109–114]. For this reason in 1995 we sought to answer the question of whether sPLA2 -IIA, similar to the situation in other inflamed sites, is expressed in atherosclerotic lesions as well [115]. Here, it could be shown that in human arterial specimens obtained after endarterectomy sPLA2 -IIA can be immunochemically identified in atherosclerotic lesions. The sPLA2 -IIA-positive immune stainings were in this study confined to regions which contained massive lipid accumulations and leukocyte infiltrations, cellular necrosis and calcifications. Sections without atherosclerotic lesions and signs of inflammatory reactions were free of sPLA2 -IIA. By using cell-specific antibodies the sPLA2 -IIA-positive cells could be identified as foam-cells, which chiefly stemmed from CD68-positive macrophages [115–117]. Although sPLA2 -IIA expressions were detectable ex vivo in neither monocytes nor in unstimulated monocyte-derived macrophages from healthy donors, sPLA2 -IIA mRNA was strongly induced after exposure of the macrophages to minimal modified and mildly oxidized LDL [118]. This suggests that the sPLA2 -II expression identified in macrophages of atherosclerotic lesions could be caused by modified LDL. Such modified lipoprotein particles are likely to occur in the subendothelial space during inflammatory reactions. Moreover, it was shown that sPLA2 -IIA, driven by its natural promoter, is also expressed in macrophages in human sPLA2 -IIAtransgenic mice [119]. In addition to macrophages and smooth muscle cells, ␣-actin-positive round cells and cells with dendrical morphology exhibited sPLA2 -IIA-positive immunostainings [116,117], whose origin is still unclear, but are possibly the same as the CD1a-positive dendritic cells described by Bobryshev et al. [120]. Further sPLA2 -IIA-positive immune reactions were found in acellular regions [115–117]. The sPLA2 -IIA exhibits a strong basic isoelectric point [10,11], so that under physiological conditions a positive net charge of the protein results and the enzyme can bind with negatively charged proteoglycans of the extracellular matrix. In a series of tissue preparations the adventitia and the smooth muscle cells in the outer layer of the media, but less the intima, were strongly stained as sPLA2 -IIA-positive [115,117]. The pathophysiological relevance of this observation is as yet unclear, also the question of how much this finding could stand in connection with the hypothesis discussed by Barker et al. [121,122] that inflammatory reactions in the vessel wall could be caused also by the adventitia via the vasa vasorum. The finding of sPLA2 -IIA expression in atherosclerotic lesions was confirmed by further studies. Hence, Bobryshev et al. [120] investigated carotid arteries and aortas and found sPLA2 -IIA-specific immunostainings in atherosclerotic

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plaques but not in areas of the adjacent normal arterial wall. Similar results have also been published by Hurt-Camejo et al. [123] and Elinder et al. [124], but in addition to atherosclerotic arteries both groups found sPLA2 -IIA-positive immunostainings in normal, non-atherosclerotic arteries. To understand the possible role of sPLA2 -IIA in the pathogenesis of atherosclerosis, the question of whether this enzyme is expressed in normal arteries is of major importance. Therefore, in a further study we investigated the sPLA2 -IIA expression in a large number of specimens taken from abdominal and thoracic aortae at autopsy and found several specimens to be free of atherosclerotic alterations exhibiting also the expression of sPLA2 -IIA [117]. In these sPLA2 -IIA-positive non-atherosclerotic tissues it could be demonstrated, however, that at the same time transcripts of proinflammatory cytokines such as IL-1␤, TNF-␣ and IFN-␥ were also present, which led to the conclusion that inflammatory processes are extant despite their morphological normality, while in the other non-atherosclerotic specimens this was not the case [117]. In the same manner atherosclerotic plaques with massive CD68-positive macrophage infiltrations without sPLA2 -IIA-positive immunostainings could be found. In these preparations there were at the same time no transcripts of the analyzed proinflammatory cytokines to be found, which leads to the conclusion that sPLA2 -IIA expression correlates very strongly with the activation status of inflammatory processes in the vessel wall. This conclusion agrees with in vitro findings as well, that in HASMC a strong sPLA2 -IIA expression occurs upon stimulation with proinflammatory cytokines [27,125,126]. In this context it should be noted that in the study published by Hurt-Camejo et al. [123] uterine arteries obtained from women undergoing hysterectomy, and in the other study, performed by Elinder et al. [124], mesenteric vessels from patients undergoing colorectal cancer surgery were applied as control non-atherosclerotic tissues. In both cases it cannot be excluded that the patients were subject to systemic inflammatory reactions accompanied by elevated cytokine levels in the blood [127,128], leading possibly to the induction of the sPLA2 -IIA expression in these arterial tissues. Because in the immunohistochemical studies monoclonal sPLA2 -IIA-antibodies were introduced to identify the enzyme in arterial tissues, whose cross-reactivity to other sPLA2 isozymes to date is not uniformly clear, we investigated along with the protein the sPLA2 -IIA expression on mRNA-level as well by using RT-PCR [117]. Here, it could be shown that in arterial areas with strong sPLA2 -IIA-immunostainings amplificates were also increasingly to be found, which in sections without sPLA2 -IIA immunostainings was not the case. The amplificates obtained agreed with the calculated magnitude for the sPLA2 -IIA, and the sequence analysis of selected amplificates also showed that the transcripts found in atherosclerotic lesions are of the group IIA [117]. In recent years the “response-to-injury”-hypothesis found increasing acceptance, in particular because along with the classical risk factors hypercholesterolemia, hypertony, the use of nicotine and diabetes mellitus, also acute-phaseproteins such as C-reactive protein (CRP) [129–131], fibrinogen [132], serum-amyloid-A [133,134], IL-6 [135] and the soluble intercellular-adhesion-molecule (sICAM) [136] have shown themselves to be an independent risk factor for coronary heart disease (CHD). In a review of the literature Haverkate [137] found that along with fibrinogen and CRP, also ferritin, the rate of blood stratification, the amount of leukocytes, Lp(a) and the level of sialinic acid in the serum as positive acute-phase-reactants, and albumin as negative acute-phase-protein were characterized in prospective studies as risk factors for CHD. Finally, the serum level of sPLA2 -IIA could be identified as a prognostic parameter for developing coronary events independent of other risk factors in prospective studies of patients with CHD [138–142]. Although the source of the serum-sPLA2 -IIA in the patients analyzed in the studies is still unclear, the inflamed sites of the vessel wall itself and the liver come under discussion. If the sPLA2 -IIA in serum really originates from the affected vessel areas, the level of serum sPLA2 -IIA could represent an important diagnostic aid for the estimation of the activity of inflammatory reactions and, in connection with that, the vulnerability of atherosclerotic plaques. Hence, it is assumed that the plaque formations, because of an amplified synthesis and secretion of hydrolases through activated inflammatory cells, become unstable and in turn leads, through the contact of plasma components with subendothelial and procoagulative structures, to a sudden occlusion of a blood vessel [143]. 4.2. Possible proatherogenic effects of sPLA2 -IIA upregulation in the vessel wall The induction of sPLA2 -IIA expression in atherosclerotic lesions can lead to a series of pathophysiological changes. In the study published by Asaoka et al. [144] an increased [3 H]-thymidine incorporation and interleukine-2-receptor expression in T-lymphocytes after incubation with sPLA2 -IIA has been described. Thus, the induction of PLA2 IIA could be connected with the activation of T-lymphocytes present in atherosclerotic plaques [145,146] and with inflammation. This occurrence is on the whole quite possibly requisite to chronic inflammation. In addition, the

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enzyme’s relative stability, due to the disulfide groups and the binding of sPLA2 -IIA on proteoglycans, enables the sPLA2 -IIA to be associated with the extracellular matrix for an extended time [147]. Furthermore, after the incubation of endothelial cells with sPLA2 -II, an increased adhesion of monocytes can be observed in vitro based on the upregulation of ICAM-1 and VCAM-1 [148]. Finally, an elevated level of PLA2 -IIA-activity can also be accompanied by altered physicochemical and biological properties of lipoproteins. Phospholipids are an essential component of lipoproteins. Because of their amphipathic properties they make possible in connection with apolipoproteins a solubilisation of the less polar lipids such as esterified cholesterol and triglycerides in an aqueous mileu. The hydrolysis of the phospholipids should for this reason lead to an altered structure and in turn to altered biological properties of the lipoproteins. Studies using electron spin resonance (ESR)-spectrometry and spin-labelled fatty acids have demonstrated that the order, micro-viscosity and polarity of lipid regions in the surface monolayer of lipoproteins increased whereas the fluidity decreased after phospholipid hydrolysis [149]. These changes point to a redistribution of free cholesterol from the core to the surface of the particles. Similar findings were made by means of NMR-spectrometry [150]. Along the same line, kinetic studies with filipin-bound cholesterol lead to the conclusion of an elevated cholesterol content in the surface of PLA2 -modified HDL3 [151]. Through the cholesterol enrichment of the particle surface a changed cholesterol gradient between lipoproteins and cell membranes emerges, which leads to an increased diffusion of free cholesterol through the aqueous phase in the direction of the cell membranes [152,153]. The binding of particles at specific cellular binding sites is unnecessary for this [154]. In the ESR investigations an altered organization of the apolipoproteins on the surface of PLA2 -modified LDL and HDL as well was observed [149]. The data point to a deeper sinking of apolipoprotein molecules in PLA2 -treated lipoproteins, by which the domains of apolipoproteins are more masked. In these studies spin-labelled analogs of maleimide were used, which bind covalently to ␣-amino- and SH-groups of apolipoproteins. These groups stretch uniformly over the entire sequence of apolipoproteins, so that nothing can be said about the behaviour of individual, narrowly defined protein regions. For this reason the reactivities of individual epitopes of apolipoprotein A-I (apoA-I) in dependence on the phospholipid content of the HDL were analyzed in competitive radioimmunoassays by using monoclonal anti-apoAI antibodies [155,156]. Here, it was shown that the immunoreactivities of selective apoA-I-epitopes after the hydrolysis of the HDL-phospholipids vary. A simple detachment of apoA-I as a result of the PLA2 treatment and reisolation of HDL after ultracentrifugation can be excluded as an explanation for these changes because the determination of the apoA-I concentrations in the HDL prior to and following PLA2 treatment showed no significant differences [156]. Likewise, after separation of apolipoproteins from the control and PLA2 -modified HDL by using SDS-polyacrylamide gel electrophoresis and after Western-blotting, no proteolytic fragments of the apoA-I could be observed, which could have lead to a changed immunoreactivity of the apoA-I as the result of a residual proteolytic activity of the porcinepancreas-PLA2 , used here as model enzyme [156]. The different immunoreactivities can thus be traced back to an altered conformation of apoA-I in PLA2 -modified HDL. Similar effects were described for sPLA2 -modified LDL as well [157]. Along with the physicochemical properties the biological properties of the LDL and HDL changed after treatment with PLA2 as well [158,159]. Thus, the incubation of macrophages with sPLA2 -modified lipoproteins led to excessive cellular lipid accumulations and transformation of macrophages into foam-like cells. Lipid-loaded foam-cells are a typical feature of early atherosclerotic lesions, which, along with smooth muscle cells, mainly stem from macrophages [160,161]. 4.3. Substrate specificities of sPLA2 -IIA 4.3.1. General enzymatic properties of sPLA2 s As with other lipases, phospholipases A2 become apparent after binding on a lipid–water interface through activation (interfacial enzymes) [162–165]. Therefore, the specific activity of these enzymes is dependent on the structure, organization and dynamics of the substrates (reviewed in Refs. [166,167]). For example, in comparison with solitary monomeric substrates, PLA2 s exhibit higher activities towards aggregated phospholipids, independent of their monolayer or bilayer structure. Also, the rate of hydrolysis of anionic phospholipids below the critical micellar concentration as well as in vesicles is considerably faster than the rate of hydrolysis of monomeric or aggregated zwitterionic phospholipids under comparable conditions [168–173]. Similar behaviour could be observed with sPLA2 -IIA secreted by HepG2 cells [174]. In the initial stage of the catalytic turnover cycle, the sPLA2 s in the aqueous phase bind to the interface along an interfacial-binding surface (i-face). Kinetic and crystallographic studies have established that sPLA2 s exhibit an

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i-face which is topologically distinct from the catalytic site, although a regulatory cross-talk between the two may exist [167,175]. Thus, the substrate specificity of sPLA2 s is dictated by the type of substrate interface to which the enzyme prefers to bind (interfacial specificity) and the type of phospholipids that are accommodated in the catalytic site (catalytic site specificity). Pig and bovine sPLA2 -modified at the catalytic site (His-48) binds to micelles, which suggests that the catalytic site is not required for binding micellar interface [166,167]. The binding of sPLA2 s to the substrate interface is modulated by (i) the substrate to additive ratio, (ii) the lateral pressure and phase-separation properties and (iii) by the physical factors including temperature, pH and the nature and concentration of ions [166]. After binding and possible structural changes, catalytic turnover events at the active site of the bound enzyme follow, which include substrate binding in the catalytic site, chemical substrate hydrolysis and release of products [166,167]. In the scooting mode the bound enzyme does not leave the vesicle and the integrity of the hydrolysed vesicles is maintained [172,176–183]. The interfacial preference for anionic interface surfaces of several sPLA2 s may be of physiological importance. Specifically, sPLA2 -IB and sPLA2 -IIA require anionic charges at the interface in order to attain optimal activity [184–187]. The physiological consequence of this activation is consistent with the environment of the natural substrate for the pancreatic sPLA2 -IB that is codispersed with anionic bile salts. In the case of sPLA2 -IIA, the interfacial binding specificity may explain why the phospholipid monolayers of native lipoproteins and the external plasma membrane of resting mammalian cells, which are both rich in zwitterionic phosphatidylcholine (PC), are normally resistant to degradation by sPLA2 -IIA. 4.3.2. Low substrate specificity of sPLA2 -IIA to native lipoproteins Since the investigations of the physicochemical and biological properties of PLA2 -modified lipoproteins have been all carried out with model enzymes like the porcine PLA2 of type IB, the next question to arise had to do with the extent to which in atherosclerotic lesions the observable human sPLA2 -IIA also modifies lipoproteins. Hence, we incubated isolated HDL and LDL with serum samples which contained elevated PLA2 -IIA concentrations, such as, for example, from patients with septic shock or acute pancreatitis, or with conditioned cell culture medium of HepG2 hepatoma cells after stimulation with IL-6 and TNF-␣. Here, however, no significantly increased concentrations of free fatty acids or altered electrophoretic mobility of lipoprotein particles could be observed. How then is the missing hydrolysis of the lipoprotein phospholipids to be explained? The investigations of the biochemical properties of the HepG2-specific sPLA2 -IIA showed that this enzyme possesses 14 times the substrate specificity for phosphatidylethanolamine (PE) in comparison with PC [174]. The phospholipids of the HDL were comprised, however, of up to 74% PC and only up to 3% of PE [188]. With LDL the behaviour is similar, such that the small portion of PE can be seen as a cause for the missing hydrolysis. Along with the preferred hydrolysis by PE we found also an inhibition of sPLA2 -IIA activity by the amphipathic apolipoproteins apoA-I and apoA-II, from which the missing hydrolysis of HDL-phospholipids is explainable as well (Fig. 1). Through elevated enzyme concentrations the inhibiting effect of the apoA-I was neutralised (Fig. 1C). This observation points to a competition between amphipathic apolipoproteins and the enzyme (“substrate depletion model” [189]). The more efficient inhibitory effects of the apoA-II in comparison to apoA-I (Fig. 1B) can be laid to a higher affinity of the apoA-II to phospholipids. It is known that apoA-II is able to displace apoA-I from egg PC and HDL, demonstrating a higher binding affinity of apoA-II in comparison to apoA-I to surface lipid monolayers [190,191]. Poensgen [192,193] described a similar PLA2 inhibition, just as that found for apoA-I and apoA-II, with bee venom PLA2 after incubation with the apolipoprotein apoC-I, which is also an amphipathic protein. Because of the competition between PLA2 -IIA and apolipoproteins for the substrate, the further question arose as to how far sPLA2 -IIA, isolated from a HepG2 conditioned cell culture medium and freed of possible inhibitors, accompanies the hydrolysis of lipoprotein phospholipids. Previous investigations showed that in HepG2 cells IL-6 and TNF-␣ induce an mRNA, which was homologous to the sPLA2 -IIA-mRNA isolated from atherosclerotic plaques [174]. The incubation of LDL or HDL with the isolated sPLA2 -IIA led finally to a significant modification of the lipoproteins [174,194]. This was mirrored in an increased anodic migration of lipoproteins in the agarose gel electrophoresis as well as in an increased concentration of free fatty acids. Indeed the enzyme activity necessary for these modifications is at approximately 6000 U/l, which is markedly higher as the observable activities in the serum of patients with severe inflammatory disorders, in which maximum values of roughly 1000 U/l were reached by using 14 C-oleate-labelled Escherichia coli-membranes as substrate. The activities in the serum of healthy specimens in this test were <1.1 U/l [195].

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Fig. 1. Inhibitory effects of apoA-I and apoA-II on the sPLA2 -IIA isolated from HepG2 cell medium after stimulation wit IL-6 and TNF-␣. After delipidation of HDL, apolipoproteins were isolated by using preparative isoelectric focusing and gel permeation chromatography. (A) Shows a stained SDS-polyacrylamide gel with apolipoproteins of HDL before and after isolation: lanes 1 and 8, molecular weight standards: 94, 67, 43, 30, 20.1, and 14.4 kDa; lane 2, human serum; lane 3, apolipoproteins of VLDL; lane 4, apolipoproteins of HDL reduced with dithiothreitol; lane 5, isolated apoA-I; lane 6, isolated apoA-II and lane 7, non-reduced apolipoproteins of HDL. (B) Relative release of fatty acids from monomer dispersed 0.38 nmol 14 C-phosphatidylethanolamine through 1.2 pg/ml HepG2 -specific sPLA2 -IIA in the presence of increasing concentrations of apoA-I and apoA-II. (C) Relative release of fatty acids from 0.38 nmol 14 C-phosphaditylethanolamine in the presence of constant amounts of apoA-I (3.5 pmol/l) and increasing concentrations of HepG2 -specific sPLA2 -IIA.

Although in vitro a phospholipolysis of native lipoproteins was observable only with quantities of enzymes not found in the serum samples, other conditions could prevail in vivo. Thus, it is conceivable that on local positions such as, for example, in atherosclerotic lesions, the sPLA2 -IIA occurs in a concentration which actually leads to a modification of native lipoproteins. The sPLA2 -IIA is characterized by a high hydrophobicity and a positive net charge [171], which leads on the one hand to an unspecific binding of the enzyme to cell membrane phospholipids, and on the other to a binding with anionic sulfated glycosaminoglycan chains of proteoglycans such as heparin and heparan sulfate. Furthermore, increased hydrolytic activity of sPLA2 -IIA toward PC of LDL after the binding of the enzyme on matrix proteoglycans has been described [196]. In comparison to sPLA2 -IIA which acts on anionic phospholipids in marked preference to charge-neutral PC, sPLA2 X and -V exhibit much more potent PC-hydrolysing activity including lipolytic modifications of native lipoproteins [197,198]. Here, it appears that the absence of certain tryptophan residues on the putative interfacial binding surface of the sPLA2 -IIA is responsible for the weak binding. Thus, the special importance of Trp31 and Trp67 for the binding of sPLA2 -V and sPLA2 -X isozymes on PC vesicles has been shown [186,199,200], which with sPLA2 -IIA are absent. This fits as well the notion that the exchange of Val3 with Trp in sPLA2 -IIA led to a strong increase in the affinity of the enzyme on PC vesicles [201]. Further studies have established that LDL modified through incubation with sPLA2 -X were efficiently incorporated into macrophages to induce the accumulation of cellular cholesterol ester and the formation of macrophage foamcells in vitro [197]. Moreover, sPLA2 -X and sPLA2 -V efficiently hydrolysed PC in HDL linked to the generation of large amounts of unsaturated fatty acids and lysophosphatidylcholine [198]. The modification of HDL by sPLA2 -X or -V resulted in a significantly decreased capacity of HDL to mediate cellular cholesterol efflux from lipid-loaded macrophages suggesting a reduction of their antiatherogenic functions. These data, in conjunction with the observations that the sPLA2 -X and -V are expressed in regions of lipid accumulation for Watanabe heritable hyperlipidemic (WHHL) rabbit, mouse and human aortic lesions [198,202], indicate that both isozymes in comparison to sPLA2 -IIA are possibly better candidates to mediate foam-cell formations in the vessel wall. It follows that several mice strains known to be susceptible to atherosclerosis are sPLA2 -IIA-deficient because of a natural mutation in exon 3 of the sPLA2 -IIA gene [55], suggesting that this isozyme is not absolutely necessary for the development of atherosclerotic lesions. 4.3.3. Failed substrate specificity of exogenously added sPLA2 -IIA to normal cell membranes There is increasing evidences suggesting that sPLA2 -IIA cannot digest membranes of healthy cells. At the root of this is, on one hand, the fact of the distribution of the preferential substrates PE and phosphatidylserine predominantly in the inner leaflets of the bilayer membranes of normal cells and, on the other, the weak binding capacity of sPLA2 IIA to PC vesicles or PC enriched in the external surface of the cell membrane [203,204]. Along with the weak

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binding capacity of the enzyme to PC vesicles and external cell surfaces agents such as lipocortins and annexins are known, which like the amphiphatic apolipoproteins can bind with phospholipids, and thus hinder the hydrolysis of the membrane phospholipids of normal cells by the sPLA2 -IIA [205]. Still further, the possibility exists that protein receptors of sPLA2 -IIA can protect healthy cell membranes from the hydrolytic action of extracellular sPLA2 -IIA [206]. Similar to native lipoproteins, sPLA2 -V and -X isozymes are more efficient in membrane hydrolysis and releasing of arachidonic acids from resting mammalian cells than the sPLA2 -IIA [200,207,208]. Thus, adding small amounts of human group X to mammalian cells leads to rapid plasma membrane hydrolysis associated with arachidonic acid release [200,207,209]. Although, in contrast to sPLA2 -IIA, human sPLA2 -V may also release arachidonic acid from resting cells, its specific activity for the hydrolysis of mammalian cells is at least six-fold less than that for sPLA2 -X [208]. This behaviour is consistent with the higher specific activity of sPLA2 -X versus sPLA-V on PC vesicles [208]. In addition to sPLA2 -IIA, the other human sPLA2 isozymes sPLA2 -IB,-IID,-IIE,-IIF and -XII also fail to liberate arachidonic acid from cells when added up to 1 ␮g/ml. All of the above isozymes display low specific activities on PC vesicles [207]. As noted already, mutagenesis studies demonstrated that tryptophan on the membrane-binding surface of sPLA2 -X and sPLA2 -V is a key residue for supporting high affinity binding to PC-rich membranes [186,199–201]. In contrast to exogenously added sPLA2 -IIA, mammalian cells transfected with sPLA2 -IIA liberate arachidonic acid although these cells are even resistant to high exogenous enzyme concentrations [8,208]. A recent study which applied the cell-impermeable sPLA2 inhibitor Me-Indoxam on these transfected cells, demonstrated that sPLA2 -IIA may act intracellulary without being secreted and acting in an autocrine manner [210]. These data suggest that the sPLA2 -IIA may be directly involved in the arachidonic acid release, providing the enzyme is upregulated in different cells. In addition to the effects which are associated with the release of arachidonic acid, the upregulation of sPLA2 -IIA can also lead to effects which are independent on its enzyme activity. Thus, catalytic inactive sPLA2 -IIA mutants which were incapable of promoting arachidonic acid release from cytokine-primed connective tissue mast cells, retain their ability to enhance COX-2 expression in these cells, indicating that the COX-2-inducing activity of sPLA2 -IIA is independent of their catalytic functions [211]. In mesangial cells and vascular smooth muscle cells, autocrine and paracrine transcriptional regulation of sPLA2 -IIA gene is found to be independent of enzyme activity [212,213]. Furthermore, sPLA2 -IIA may activate signaling pathways such as protein kinase C, MEK/ERK1/2, p38 MAPK and PI3K/Akt cascades [214–218], as well as the synthesis and release of cytokines from human monocytes, lung macrophages and eosinophils, for which in part the enzyme activity is not required [219–222]. Similarly, enhanced survival signals in mast cells have been demonstrated for pancreatic sPLA2 -IB and bee venom sPLA2 -III which are probably mediated via sPLA2 receptors rather than sPLA2 catalytic products [223]. The presence of such sPLA2 receptors has been documented on a variety of cells, including smooth muscle, fibroblasts, polymorphonuclear neutrophils (PMN), Swiss 3T3 cells and astrocytes [4,218,224–228]. Two distinct sPLA2 receptors are known: the M-type, present on smooth muscle and the N-type, found on cells of neural lineage [224–227]. These receptors may serve important physiological functions as ligand occupancy affects cell physiology, manifested by migration and proliferation of vascular smooth muscle cells, adhesion of PMN and activation of p38 MAPK connected with elastase release, inhibition of acetylcholine release, proliferation of Swiss 3T3 cells and tumor invasion [218,229–233]. Considering the great number of different effects which are independent of the activity of sPLA2 -IIA, this may provide an explanation for the unexpected results of two recently published clinical trails applying selective sPLA2 IIA inhibitors. In the clinical study on 373 patients, which we mentioned earlier, the inhibition of sPLA2 -IIA by LY315920NA/S-5920 did not only fail to improve the clinical outcome, but also revealed a negative trend in the 28-day-all-cause mortality. The mortality in the treatment group was 39.4% in comparison to 31.9% in the placebo group (relative risk, 1.23; 95% confidence interval, 0.94–1.63) [26]. The results from a second clinical trail, in which LY333013 as an sPLA2 -IIA inhibitor was tested, suggested an inefficiency of the drug after a 12-week treatment of active rheumatoid arthritis [234]. In addition to the effects which are independent of sPLA2 -IIA activity and therefore not blocked by the applied drugs, an inhibition of the enzyme activity can be linked to a reduced bactericidal capacity. This may, at least in the case of the first study, give a further explanation for the disappointing clinical results. These data emphasize the importance of understanding the detailed physiological and/or pathophysiological functions of the sPLA2 -IIA including the other sPLA2 isozymes during inflammation.

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4.3.4. Increased susceptibility of oxidatively modified lipoproteins to sPLA2 -IIA Along with a possible local enrichment of sPLA2 -IIA through its hydrophobic and cationic character, investigations in vitro have shown that after mild oxidation induced by copper ions or 2,2-azobis (2-amidininopropane), the susceptibility of LDL to sPLA2 -IIA-mediated phospholipid hydrolysis increased [174]. It can be assumed that during inflammatory reactions strongly oxidatively modified lipoproteins emerge in the vessel wall, which for its part represents a suitable substrate for the sPLA2 -IIA expressed within the wall. Moreover, LDL hydrolysed by PLA2 is more susceptible to lipid peroxidation, as shown, that PLA2 activity enhanced endothelial cell modification of LDL, through which they exhibited in turn an increased affinity to proteoglycans and length of their tenancy in the vessel wall increases [196,235]. Furthermore, it was found that lipoproteins like HDL are a suitable substrate for sPLA2 -IIA during an acute-phase-reaction [236]. All these results led for this reason to the conclusion that sPLA2 -IIA expression in the arterial wall should be associated with proatherogenic effects and that sPLA2 -IIA represents a possible link between chronic inflammation and lipid accumulation in the vessel wall, in that the enzyme in the subendothelium during inflammation hydrolyses intensively formed, oxidatively modified lipoproteins and thus contributes to an amplified formation of foam-cells if this process continues excessively. 4.3.5. Increased susceptibility of injured and apoptotic cell membranes to sPLA2 -IIA Under certain conditions such as during apoptosis or after cellular trauma, which are associated with oxidative stress and cellular injury, cell membranes and microvesicles shed from activated cells become also highly susceptible to sPLA2 -IIA [237,238]. Being looked at along with alterations in the phospholipid integrity of the cellular membrane is as well an increased exposition of PS and PE on the outer surface of these cells as causes of this [239–245]. Recent evidence suggests that sPLA2 -IIA does not absorb to cell membranes unless phosphatidylserine has been exposed on the outer leaflet of the cell membrane [203,204]. In these occurrences the intracellular calcium level plays a central role as the calcium entry during cell injury results in exposure of the anionic phosphatidylserine similar to that observed during apoptosis (reviewed in Ref. [246]). Beyond that it could be observed that following incubation of human neutrophile-like cells and erythrocytes with an ionophore to increase intracellular calcium level, the phospholipids of the cell membrane became susceptible to sPLA2 -IIA [247,248] and that the effect of calcium involves physical changes in membrane structures [199]. Moreover, it has been found that vimentin, in conjunction with heparan sulfate proteoglycans, contributes to the enhanced binding of sPLA2 -IIA to apoptotic T cells and that specific motifs in the i-face are involved in the interaction with vimentin [249]. To the question of the susceptibility of sPLA2 -IIA to cell membranes cell-type-specific differences were observed. Whilst intact smooth muscle cells, endothelial cells, hepatocytes or myocytes, for example, were resistant to injury by mammalian sPLA2 -IIA [6,81], in primary cultures of cortical neuronal cells and astrocytes sPLA2 -IIA itself can trigger cell death via an apoptosis [250,251]. Also, after deprivation of nerve growth factor, serum or hematopoietic cytokines from the culture medium, neuronally differentiated PC12 cells or mast cells were made accessible for a sPLA2 -IIA-mediated cell membrane phospholipid hydrolysis and release of arachidonic acid, after the cells showed signs of apoptosis. A similar result could be established on U937 monocytic leukemia cells after stimulation with anti-Fas antibodies [237]. An intensified eicosanoid synthesis could be likewise observed after the appropriate cell activation, e.g., by TNF-␣ in human umbilical vein endothelial cells [252] and in rat hepatic BRA-3A cells [253] as well as in IgE-sensibilized rat mast cells [254] with exogenous sPLA2 -IIA. Finally, a phospholipid hydrolysis has been described in intact cells in the presence of sphingomyelinase [238], which in the context of the observable sPLA2 -IIA in atherosclerotic lesions is of interest due to the simultaneous occurrence of an acid sphingomyelinase in atherosclerotic lesions [255]. 4.4. In vivo data indicating a role of sPLA2 -IIA in the lipoprotein metabolism Studies on transgenic mice documented that a phospholipid hydrolysis of lipoproteins by human sPLA2 -IIA takes place in vivo as well [119,256–258]. Thus, in transgenic mice, which overexpress human sPLA2 -IIA, observations of significantly higher serum concentrations of free fatty acids and depressed plasma cholesterol levels, altered lipoprotein compositions were noted, indeed in the absence of inflammatory reactions in the transgenic animals themselves. The analysis of lipoprotein subfractions by ultracentrifugation as well as by agarose gel electrophoresis and subsequent staining of cholesterol including densitometric analysis indicated that the reduction of plasma cholesterol was due to decreased concentrations of both LDL and HDL cholesterol [257]. Similar data were obtained after cholesterol-rich

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diet over 13 weeks, where the transgenic mice in comparison to the control animals exhibited reduced concentrations of HDL and the ␤-lipoproteins (␤-VLDL and LDL) as well [259]. The determination of the mean mass composition of LDL demonstrated that although the amount of the particles was not altered, LDL of transgenic mice were selectively depleted in free and esterified cholesterol [257]. On the other hand, the LDL were enriched with triglycerides, suggesting an exchange of cholesterol esters with the triglycerides. Interestingly, similar data were reported by Sammalkorpi et al. [260] for human LDL during acute viral and bacterial infections, where the particles were found to be triglyceride-rich and cholesterol-poor, depending on the severity of infection. In contrast to LDL, the protein concentration of HDL in sPLA2 -IIA-transgenic mice was significantly lower in comparison to the controls, suggesting that the number of HDL particles decreased in the plasma of sPLA2 -IIAtransgenic mice [256,257]. Furthermore, both the concentrations of free and esterified cholesterol as well as the concentrations of phospholipids were reduced. These data provide evidence that, in contrast to LDL, the decreased HDL cholesterol concentration in the plasma of transgenic mice is due to enhanced metabolism of HDL as whole particles. It is noteworthy in this context, that in cultures of human skin fibroblasts a limited cellular degradation of sPLA2 -modified LDL was found, whereas an uptake and degradation of sPLA2 -modified HDL have been described after exposure to rat hepatocytes [157,261]. Similar data were described by showing that the fractional catabolic rate of [125 J]-HDL was significantly faster in sPLA2 -IIA-transgenic mice compared with control littermates [262]. Still further, the same research group found that through the sPLA2 -IIA expression the catabolic rate of apoA-I climbed, but that of the apoA-II remained unchanged. It is known, as already mentioned, that apoA-I binds less tightly to lipids than does apoA-II [190,191]. Possibly because of the sPLA2 -IIA, apoA-I is pushed more easily than apoA-II from the HDL. As a consequence different susceptibility and, in a related sense, different catabolic rates of HDL subfractions containing apoA-I compared to those containing apoA-I and apoA-II during the inflammation could be the result of this. Whereas in the work published by de Beer et al. [256] likewise significantly lower HDL cholesterol concentrations in transgenic animals were found when compared to non-transgenic littermates, no alterations in the metabolism of LDL in transgenic mice could be found. The most likely explanation for this discrepancy lies in the existence of differences in sPLA2 -IIA activities of the transgenic mice. By applying [14 C]-oleate labelled E. coli-membranes as substrate we measured a mean sPLA2 -IIA activity of 331 U/l in serum of transgenic mice and in control animals a sPLA2 -IIA activity below the analytical sensitivity of <0.5 U/l. This ratio of activities was remarkably higher in comparison to those reported by de Beer et al. [256] who measured an eight-fold higher sPLA2 -IIA activity in transgenic compared to non-transgenic littermates. The differences concerning the expression of human group IIA sPLA2 in transgenic mice are important because of the finding that the physicochemical and biological properties of lipoproteins alter in dependence on the degree of phospholipolysis and thus on the level of sPLA2 activity [149,150,157–159,261,263]. On the other hand, the transcription of the human sPLA2 -IIA gene changed in the course of the study and was dependent on the age of the animals [101,259]. Taken together, disregarding the mentioned differences concerning the LDL metabolism in sPLA2 -IIA-transgenic mice, all studies on this transgenic mice model suggest that a relationship exists between the elevated serum sPLA2 -IIA activity and the development of hypocholesterolemia during inflammation. Patients suffering from inflammatory diseases were frequently found to have decreased plasma concentrations of total cholesterol, LDL and HDL cholesterol [260,264–270]. Windler et al. [271] have shown in severely ill patients that the concentration of serum cholesterol can reach very low levels and that the prognosis was reflected in the degree of hypocholesterolemia. Due to the strong correlation, the authors concluded that the cholesterol level of severely ill patients might serve as a clinical prognostic parameter. Numerous clinical and epidemiological studies demonstrated that an inverse correlation between the serum cholesterol concentration and the expression of proinflammatory cytokines in patients with inflammatory diseases exists [272–274]. Furthermore, it was demonstrated that after application of proinflammatory cytokines or the use of other inflammatory stimuli, a rapid fall in the concentration of total plasma cholesterol occurs in mammals [270,274–278]. Various hypotheses were considered to explain the relationship between the expression of cytokines and the low concentration of serum total cholesterol during inflammatory processes. Cytokines were found (i) to upregulate the LDL receptor activity [279,280], (ii) to decrease the lecithin:cholesterol acyltransferase activity [277], (iii) to reduce the hepatic synthesis and secretion of apolipoproteins A-I and B [281] and (iv) to increase the catabolic rate of lipoproteins [273,274]. On the other hand, cytokines such as interleukin-1␤, interleukin-6 and tumor necrosis factor-␣ are known to induce the synthesis and secretion of sPLA2 -IIA and the high plasma sPLA2 -IIA activities in patients with inflammatory diseases are ascribed to the action of such cytokines [83]. Therefore, the findings on sPLA2 -IIA-transgenic mice suggest

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Fig. 2. Monitoring of serum HDL and LDL cholesterol (A) in relation to serum concentrations of C-reactive protein (CRP), procalcitonin and sPLA2 -IIA of a 67-years old male patient suffering from sepsis. The first serum analysis started with the referral of the patient into the intensive care-unit.

that the induction of sPLA2 -IIA, resulting in phospholipolysis of LDL and HDL and an increased catabolic rate of these lipoproteins, may be an additional mechanism by which proinflammatory cytokines can cause hypocholesterolemia. To demonstrate the possible relationship between the hypocholesterolemia and the sPLA2 -IIA upregulation, Fig. 2 shows a representative example of the kinetic course of HDL and LDL cholesterol and the concentrations of sPLA2 -IIA, C-reactive protein (CRP) and procalcitonin (as a marker of bacterial infection [282]) in serum of a patient with septic disease. 4.5. Increased susceptibility of sPLA2 -IIA-transgenic mice to atherosclerosis That in vivo a sPLA2 -IIA expression in the vessel wall is accompanied by an intensified formation of atherosclerotic lesions, is argued by the findings published by Ivandic et al. [283]. In this way, following a 12-week high-fat, highcholesterol diet, increased fatty streak lesions in the aortic sinus of sPLA2 -IIA-transgenic mice along with sPLA2 -IIApositive immunostainings could be demonstrated, whose total areas were about six-fold greater in male transgenic mice by comparison to those of their non-transgenic male littermates [283]. The lesion areas of female transgenic animals were about twice those of female littermates. Moreover, in mice maintained on a low-fat, solid-food diet significant lesions were observed in transgenic animals, whereas in control animals no lesions or very small lesions were found. The transgene of the mice was constructed in such a way so as to permit the regulation of the transgene by its natural promoter. As a possible cause for the rise in lesion development in the transgenic mice, the reduced HDL level and the elevated VLDL/LDL level as well as the reduced level of paraoxonase, an enzyme associated with HDL that protects against LDL oxidation, were discussed [283]. That, however, an altered lipoprotein metabolism need not be a prerequisite for intensified lesion formation, has been shown by investigations on LDL receptor knockout mice (LDLR−/− ), reconstituted with bone marrow cells expressing human sPLA2 -IIA [119]. Thus, after 12 weeks of maintaining these animals on a cholesterol-rich diet, the LDLR−/− /sPLA2 -IIA+/+ mice developed significantly larger lesions in the aortic arch (73% increase) and aortic sinus

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(50% increase) without exhibiting any changes in serum lipoprotein concentrations by comparison to those of control mice with wild-type bone marrow cells. By using the myeloid-specific CD11b promoter instead of the sPLA2 -IIA’s own promoter fused with the human genomic sPLA2 -IIA gene, a macrophage human sPLA2 -IIA overexpression model was generated [284]. Bone marrow from this model was then transplated to LDLR−/− mice and the effect of a local macrophage-specific vascular sPLA2 -IIA expression were investigated. After a 10-week high-fat diet the analysis of the aortic root, near the heart valve, indicated that the sPLA2 -IIA expressed in macrophages resulted in a 2.3-fold increase in the lesion size [284]. Finally, a macrophage-specific overexpression of human sPLA2 -IIA was found to increase the atherogenesis by directly modulating oxidative stress in vivo [285]. If one summarizes the data described until now, then it can be ascertained that a host of data in vitro and in vivo on proatherogenic effects in the elevated expression of sPLA2 -IIA in atherosclerotic lesions is indicated. Numbering among these is that first, the sPLA2 -mediated hydrolysis of phospholipid monolayers of LDL and HDL resulted in a shift of unesterified cholesterol from the core to the surface of the particles, which is likely to facilitate the cholesterol transfer to cells. This may explain why the exposure of macrophages to sPLA2 -modified LDL and HDL was followed by increased cellular lipid accumulations transforming them into foam-like cells. Second, mitogenic effects of sPLA2 IIA were described on VSMC [286]. Third, sPLA2 -IIA has been identified in human atherosclerotic lesions, where it was predominantly located in macrophages, CD1a-positive dendritic cells and smooth muscle cells, but no sPLA2 -IIA expression was observed in the unaffected parts of the arterial wall without signs of ongoing inflammatory reactions. Fourth, it was established that in transgenic mice an overexpression of the human sPLA2 -IIA gene exhibited enhanced atherosclerotic lesions in the aortae of these animals by comparison to their non-transgenic littermates. And finally, prospective studies point to sPLA2 -IIA as an independent risk factor in the development of CHD. 5. Data suggesting alternative functions of sPLA2 -IIA during inflammation While the investigations described up to now permit the conclusion that in the case of sPLA2 -IIA, due to proinflammatory and proatherosclerotic effects, a pathogenic factor during inflammation is involved, new studies provide evidence that a protective function of sPLA2 -IIA is also indicated. 5.1. Bactericidal properties of secretory phospholipases A2 In the case of mammals, numerous different peptides and polypeptides are found, which are able to kill staphylococci and other Gram-positive bacteria. In this, the sPLA2 -IIA is included, which is an exceptionally efficient bactericidal agent. Already at the end of the 1970s, Elsbach et al. [287] were able to isolate from rabbit-leucocytes a PLA2 , which in vitro in combination with a second protein, the bactericidal/permeability-increasing protein (BPIP), effectively killed Gram-negative strains of E. coli and Salmonella typhimurium. Later, an antibacterial effect against Staphylococcus aureus in inflammation exudates was found, which likewise could be traced to sPLA2 [288,289]. Bactericidal properties against Gram-positive bacteria were also verified in years following for human sPLA2 -IIA, and high concentrations of the enzymes in inflammation exudates [290] and in tear fluid [291] speak likewise for the antibacteriological function of the enzymes. In addition, the enzyme is released by intestinal Paneth-cells and by macrophages [290], both cell types are involved in the body’s defense against bacteriological intruders. Thus, the sPLA2 -IIA isolated in murine small intestine was able to kill both E. coli and Gram-positive Listeria monocytogenes [292]. It is presumed that the ability of sPLA2 -IIA to attack S. aureus and other Gram-positive bacteria lies primarily in the enzyme, in the binding to the bacterial cell wall, the penetration of the wall and the hydrolytic attack on the phospholipids of the bacterial cell membranes [293,294]. The initial binding of sPLA2 -IIA to the cell surface of S. aureus is based upon electrostatic interactions between sPLA2 -IIA and the cell surface. Among the more than 100 structurally very similar low molecular sPLA2 (14–19 kDa) sPLA2 -IIA is unique in its extremely high positive net charge of between >12 and >17 [295]. This high net basicity is seen as the reason for the effective antibacteriological activity of sPLA2 -IIA against Gram-positive bacteria [296,297]. New investigations, in which the potency of human sPLA2 ’s against Grampositive bacteria were compared, showed the following ranking order: sPLA2 -IIA > X > V > XII > IIE > IB = IIF [21]. The requirement of sPLA2 -IIA activity to kill bacteria efficiently was demonstrated by addition of EGTA, showing the calcium-dependency and by alkylation of the enzyme preventing the bacterial killing [289,292]. It is interesting that despite attacks by sPLA2 -IIA, S. aureus and Micrococcus luteus to a certain degree are in a position to synthesize de novo phospholipids and thus to use the resulting products of the reaction of sPLA2 -IIA-mediating hydrolysis for their

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own resynthesis [298]. Only with a phospholipid hydrolysis of more than 60% does an effective killing of bacteria take place. Furthermore, the killing efficiency against differing bacteria strains in comparison with the amount of sPLA2 -IIA also depends upon the presence of endogenous “enhancing factors”, like lysozyme and other antibacterial peptides or proteins, which disrupt the bacterial cell wall, thus allowing the enzyme to penetrate the anionic peptidoglycane cell wall and in turn giving it accessibility to the plasma membrane (reviewed in Refs. [293,299]). Finally, the protective effect of the sPLA2 -IIA against Gram-positive and Gram-negative bacteria could be verified also in vivo through investigations of sPLA2 -IIA-transgenic mice. In this way, the transgenic mice when compared with the control animals showed a significantly higher resistance to S. aureus [18]. While the majority of the transgenic animals showed only minor symptoms of sepsis and remained completely alive after having received an i.p. injection of S. aureus, after 24 h 85% of the non-transgenic control animals had already died. The deceased animals exhibited severe congestion of the lung, liver and kidneys and accumulation of hemorrhagic exudate in the pleural and peritoneal cavities. Later, the same group could also verify a higher resistance of the sPLA2 -IIA-transgenic animals to Gram-negative E. coli bacteria in comparison to the control animals [19]. Despite intensive research and advances in diagnostics and therapies, the mortality of severe sepsis at 30% and septic shock at 50–60% is still very high, putting sepsis among the leading cause of death in non-cardiological intensive care units [300–302]. In the last few years, the understanding of sepsis has changed fundamentally. Sepsis was until now seen exclusively as a reaction to an infection that had gone out of control, and based upon this, had set up antiinflammatory prevention and therapy, e.g., through the use of antibodies against endotoxin, different cytokines or their receptors. Thus, new investigations show that with elevated cytokine levels not only a damaging, rather also a protective effect can be observed (reviewed in Ref. [303]). Investigations on laboratory animals with peritonitis showed, for example, that after the blockage of the TNF-␣, the survival rate of the animals declined [304,305]. A combination therapy against TNF-␣ and the IL-1-receptor was likewise fatal for a neuropenic model of sepsis [306]. Even in a clinical study in which TNF-␣ antagonists were administered, the mortality rose [307]. The importance of cytokines, especially of TNF-␣, also is apparent in patients with rheumatoid arthritis. In the case of patients who have been treated with TNF-␣ antagonists, sepsis occurred at a higher rate or with infectious complications [308]. The ultimate cause of death in patients with sepsis is still unclear. An absence of acute-phase-reactants in the case of patients with sepsis is, however, associated with a high mortality rate [303]. While through a blockage of the proinflammatory cytokines no far-reaching successes in the treatment of sepsis patients were to be noted, by the substitution with recombinant activated protein C (APC) in the PROWESS study an improved treatment could be developed [309,310]. Thus, the risk of death fell by 19.4% for patients with sepsis, the absolute risk by 6.1% [309]. APC deactivates the coagulation factors Va and VIIIa and so hinders the formation of thrombin [310]. However, that the efficiency of APC is not solely attributable to the inhibition of the coagulation process was shown by investigations with two further anticoagulants, antithrombin III and inhibitors of the tissue factor. In contrast to APC the dosages of both coagulation inhibitors did not lead to an improved rate of cure in the septic patients [311]. An explanation for this could lie in that these inhibitors, by comparison to APC, have an effect upon other points of the coagulation system. Furthermore, they are verifiable for the APC antiapoptotic characteristics [312], which until now has not been the case for both of the other inhibitors. The investigations on the transgenic mice underline the notion that sPLA2 -IIA expression leads to an improved resistance to bacteriological infections. Although these data cannot simply be transferred to the bacteriological infections of humans as far as sepsis, the question remains as to the degree to which the highly upregulated human sPLA2 -IIA in fact does not work bactericidally and whether a suppression of the enzyme is indeed counterproductive in the prevention and therapy of sepsis. In this connection there are several studies which are of special interest in respect of the effects of statins in the course of sepsis, especially when the finding is considered that statins amplifiy the cytokine-induced sPLA2 -IIA synthesis and secretion in different cell systems [27,31]. Thus, first, in a retrospective review of 388 patients with bacteremic infections due to Gram-negative bacilli and S. aureus, it was shown that the mortality among patients taking statins in comparison to patients not taking statins was significantly reduced (6% versus 28%; p = 0.002) [313]. Second, similar beneficial effects of statins have been described in mice with lipopolyssaccharide-induced sepsis where the treatment with cervistatin significantly reduced the mortality relative to the untreated control animals (73% survival in statin-treated animals versus 27% survival in control animals at 7 days; p = 0.016) [314]. Third, in a recently published study the mean survival period of simvastatin-treated mice rendered septic by cecal ligation and perforation was increased nearly four-fold in comparison to the untreated animals (108 h versus 28 h for untreated animals; p < 0.005) [315]. Finally, in a prospective, observational cohort study of 361 severely ill patients, where 82 of these patients had

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been taking statins prior to their illness and 279 had not, a severe sepsis developed in 19% of patients in the non-statin group and in only 2.4% of the statin group (p < 0.001) [316]. Why do statins appear to improve outcomes in critical illness, and could a possibility arise out of this for the primary prevention of severe sepsis? On the one hand statins are believed to have antiinflammatory and immunomodulatory properties quite independent of their lipid-lowering abilities [317]. On the other hand, the synergism between statins and proinflammatory cytokines on the sPLA2 -IIA expression connected with efficient bactericidal protection [17–25] could represent a further mechanism for the effects of statins in the prevention and therapy of sepsis. If the potential bactericidal characteristics of sPLA2 -IIA are viewed in connection with atherosclerosis, then a mechanism could exist here as well to explain the benefit of statin treatment. As a series of studies showed, the incidence of myocardial infarction and stroke is elevated by frequent infections [318–320]. In recent years along with viral infections bacteriological infections as well have attracted interest as a possible cause of atherosclerosis [321–326]. 5.2. Antithrombotic properties of sPLA2 -IIA Just as for a number of snake-venom-sPLA2 anticoagulant activities have also been described for mammalian sPLA2 -IIA [327–332]. Based on the fact that for an efficient activation of blood coagulation the exposure of negatively charged phospholipids on cell surfaces is necessary and the sPLA2 -IIA, as already mentioned, are strongly cationic and contain a cluster of positive charged amino acid residues, there are grounds for the supposition that the sPLA2 IIA may compete with coagulation factors for the negatively charged cell surface phospholipids. Investigations on venom sPLA2 illustrate, however, that sPLA2 exerts its anticoagulant effect by means of protein–protein rather than protein–phospholipid interactions [333]. Thus, it could be shown, that the strongly basic phospholipase A2 isoenzyme (CM-IV) from Naja nigricollis venom inhibits the prothrombinase complex. After alkylation of its active-site histidine, CM-IV lost 97% of its enzymatic activity but retained 60% of its inhibitory potency on prothrombinase. Moreover, the CM-IV inhibited prothrombinase activity in the absence of phospholipids, indicating that the CM-IV-mediated inhibition of the prothrombinase complex was not due to the binding to phospholipids or its hydrolysis. In an isothermal calorimetry study in this connection, it was demonstrated as it was already found for human sPLA2 -IIA that CM-IV binds to factor Xa, but not to prothrombin or factor Va [334,335]. Furthermore, CM-IV had no effect on the cleavage of prothrombin by factor Xa in the absence of factor Va. In the presence of factor Va, however, CM-IV inhibited thrombin formation by factor Xa. If the amount of CM-IV is held constant, the concentration of factor Va rises, relieving the inhibition. Therefore, it has been concluded that the phospholipase A2 enzyme inhibits the formation of the normal Xa–Va complex by competing with factor Va for binding to factor Xa or replacing bound factor Va from the complex. Similar behaviours have been found in case of sPLA2 -IIA [334]. Indeed, human sPLA2 -IIA exhibited significant anticoagulant activity that did not require its enzymatic activity. The inhibitory effect of sPLA2 -IIA on the prothrombinase activity of FXa, FV, phospholipids and Ca2+ complex was enhanced upon the preincubation of sPLA2 -IIA with FXa, but not with FV [334]. Prothrombinase activity was also strongly inhibited by sPLA2 -IIA in the absence of phospholipids. Increased concentrations of FVa in the prothrombinase generation assay reversed the inhibitory effect of sPLA2 -IIA. Furthermore, the use of synthetic peptides in prothrombinase assays provided evidence that residues which are similar to a region of FVa that binds to FXa, are likely involved in the anticoagulant interaction of sPLA2 -IIA with FXa [334]. In a further study, it was shown that sPLA2 -IIA and its catalytically inactive H48Q mutant prolong the lag time of thrombin generation in human platelet-rich plasma with similar efficiency, indicating that sPLA2 -IIA exerts an anticoagulant effect independent of phospholipid hydrolysis under ex vivo conditions [336]. A charge reversal of basic residues on the interfacial binding surface of sPLA2 -IIA, led to a decreased ability to inhibit prothrombinase activity, which correlated with a reduced affinity for factor Xa [336]. Taken together, even though verification in vivo is still not available, that sPLA2 -IIA in humans as well acts as an anticoagulatory agent, here a further mechanism could exist to explain the benefits of statins in the prevention and treatment of both sepsis and CHD, in that in the presence of IFN-␥, through the stimulation of sPLA2 -IIA synthesis and secretion into the blood stream, statins may inhibit the formation of thrombin. One of the numerous possible complications during severe sepsis and septic shock is that microvascular thrombosis, if it becomes generalized, can cause extensive tissue ischemia connected with organ failure and death [337]. The formation of a thrombus after the rupture of atherosclerotic plaques is viewed as a sudden and fatal incident in CHD as well. A blockage of thrombin formation could, therefore, in both cases, be associated with a beneficial effect. Finally, it should also be mentioned,

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that endogenously and exogenously added sPLA2 -IIA amplified the PGI2 generation in vascular endothelial cells, which act antithrombotically, suggesting a potential role of sPLA2 -IIA as a negative regulator in blood coagulation. 5.3. Enhanced clearance of oxidative modified lipoproteins during inflammation by sPLA2 -IIA via liver and adrenals Along with its bactericidal and antithrombotic properties, the ability of sPLA2 -IIA to be able to “distinguish” between native and oxidative modified lipoproteins could suggest a further positive effect in the upregulation of sPLA2 -IIA. If one considers that during inflammation not only cytokines and sPLA2 -IIA are released at a higher rate but that also increased amounts of oxidatively modified lipoproteins are very probably produced, a beneficial mechanism could exist, which consists in the notion that oxidatively modified lipoproteins are removed from the bloodstream by organs with high sPLA2 -IIA expression, such as the liver. Speaking for this assumption is a number of data gathered on sPLA2 IIA-transgenic mice. First, the liver of transgenic mice exhibited the highest sPLA2 -IIA expression [101,102]. Second, in sPLA2 -IIA-transgenic mice, an elevated level of oxidized phospholipids was found in the liver [338]. Third, the livers of transgenic mice were found to contain significantly increased concentrations of free and esterified cholesterol by comparison to the livers of their non-transgenic littermates [259]. The hypothesis of sPLA2 -IIA-mediated clearance of modified lipoproteins through the liver is supported by further investigations. Phospholipolysed LDL injected into rabbits was shown to be removed from the bloodstream up to 17 times faster than native LDL, and the liver was identified as the organ predominantly responsible for this accelerated clearance [339]. On hypercholesterolemic rabbits, it was shown that low-density lipoproteins treated with immobilized snake venom PLA2 in an extracorporal circuit was rapidly cleared from the plasma by the liver. Based on these results, the implantation of a device containing immobilized PLA2 was suggested as a useful way to lower high plasma levels of cholesterol [339,340]. In addition, the studies published by Bamberger et al. [150,263] and Collet et al. [261] have shown that HDL modified by hepatic lipase or phospholipase A2 treatment have an enhanced ability to deliver free and esterified cholesterol to cultured hepatocytes. In humans also it is presumed that the formation of sPLA2 -IIA by the liver is elevated during inflammation as an acute-phase-reactant. In this context it can be assumed that the enzyme remains bound at first to the surface of liver cells (hepatocytes and Kupffer cells) because of its hydrophobic and cationic character and can possibly reach an appropriately high concentration. In addition to the liver, Tietge et al. [258] found also in the adrenals of sPLA2 IIA-transgenic mice a significantly higher uptake of HDL cholesteryl esters in comparison to that of control animals. The extent to which the sPLA2 -IIA-mediated hepatic and adrenal uptake of modified lipoproteins during inflammation applies also to humans is still the subject of speculation. It is conceivable, however, that for the induced synthesis of stress hormones during the acute-phase-reaction, precursors are necessary in greater amounts, as initially hypothesized by Groen et al. [341]. HDL cholesteryl esters are known as a source of cholesterol for steroid hormone synthesis [342]. With that, this mechanism would likewise be viewed as protective, since (i) the increasing accumulation of oxidatively modified lipoproteins, which has a cell-toxic effect, is filtered out of the bloodstream during inflammation and (ii) the adrenals, supplied with sufficient precursors during inflammation, which boosts corticoid synthesis. At this point it should still be noted, that the statin-mediated synergism with IL-1␤ and IFN-␥ on sPLA2 -IIA expression was not restricted to HASMC, as the same effect could be demonstrated in HepG2 hepatoma cell cultures [27]. For this reason, it is most probable that in an inflammation with elevated IL-1␤ and IFN-␥ levels, the statins increase the expression of sPLA2 -IIA in the liver, thereby accelerates the clearance of oxidatively modified lipoproteins via the hepatic tissue. 5.4. In vitro data suggesting antiapoptotic properties of sPLA2 -IIA The role played by sPLA2 -IIA during apoptosis is hence still unexplained. With the exception of neuronal-like cells, normal cells are resistant to sPLA2 -IIA hydrolysis, but after activation with different stimuli a number of cells become susceptible to sPLA2 -IIA hydrolysis [as described under Section 4.3.5]. On the other hand, in baby hamster kidney cells there is also evidence of sPLA2 -IIA-generated antiapoptotic survival signals, suggesting that high levels of sPLA2 -IIA accumulated at inflammatory sites might impact the final effect of inflammation by triggering cellprotective machinery [343]. Similarly, enhanced survival of mast cells has been demonstrated by pancreatic sPLA2 and bee venom sPLA2 isotypes [223]. Since apoptosis is seen as an essential cause, on the one hand, for the instability

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of atherosclerotic plaques and, on the other, for immune paralysis occurring with sepsis, which is often accompanied by a reduced number of lymphocytes and gastrointestinal epithelial cells [344,345], could an increased synthesis of sPLA2 -IIA and with that an increased build up of antiapoptotic survival signals, represent a positive effect here as well. 5.5. In vivo and in vitro data suggesting antiinflammatory properties of sPLA2 -IIA New studies indicate that lipid-mediator biosynthesis is biphasic, with a role for eicosanoids in the initiation as well as termination of the inflammatory response [346]. Thus, in carrageenin-induced pleurisy in rats a dual role of cyclooxygenase-2 (COX-2) has been observed [347,348]. In this model, COX-2 protein expression initially peaked at 2 h, associated with maximal prostaglandin E2 (PGE2 ) generations. At 48 h, however, there was a second peak in COX-2 expression. Paradoxically, this peak was associated with minimal PGE2 synthesis and increased levels of prostaglandin D2 (PGD2 ) and 15-deoxy-delta 12, 14-prostaglandin J2 , and coincided with inflammatory resolution [346,347]. The conclusion therefore is that COX-2 may be proinflammatory during the early phase, but antiinflammatory at the later phase of pleurisy. It is generally agreed that in the lipid mediator production on the one hand a “cross-talk” between the different sPLA2 isozymes exists, in which sPLA2 -IIA and -V are regulatory. Cytosolic PLA2 (cPLA2 or PLA2 -IV) is responsible for the release of arachidonic acid as precursor for lipid mediators. On the other hand, a functional coupling with COX-2 occurs [8,249–351]. At present, there is discussion about the participation of sPLA2 -IIA in the resolution of inflammation, as in a recently published work of the profile of different PLA2 isozymes, during which a carrageenin-induced acute pleurisy was investigated [352]. In this it was shown that the onset phase of the response is characterized by a predominant expression of calcium-independent PLA2 (iPLA2 or PLA2 of type VI) connected with the synthesis of PGE2 , leukotriene B4 , PAF and IL-1␤, while the levels of sPLA2 -IIA, sPLA2 -V and cPLA2 at this juncture were rather low. During resolution, however, this changed in the sense that sPLA2 -IIA and sPLA2 -V formation was intensified, with the consequence of increased syntheses of PAF and leukotrien-derived lipoxin A4 (LxA4 ), which induced the following expression of cPLA2 for its part. The cPLA2 in turn induces COX-2 concurrently with the proresolving PGD2 synthesis. Furthermore, indications were found, that the differing expressions of the PLA2 isozymes are connected with the local levels of endogeneous glucocorticoids. Thus, during onset a maximal level of corticosterones was verifiable in the rats, while in the latter resolving phase these sterones were undetectable. Since it is known that the in vitro expression of sPLA2 -IIA and cPLA2 is inhibited by dexamethasone [353], it can be inferred that the expression of sPLA2 and cPLA2 at the beginning of the inflammatory response is blocked by the corticosterone and in turn first induced after the corticosterone level falls off. The corticosterones are released, as the investigations on rats showed, at a very early phase of inflammation by the proinflammatory mediators IL-1␤, IL-6 and TNF-␣ via the hypothalamic-pituitary-adrenal axis [354]. Interestingly, the expression of iPLA2 remained unaffected by the addition of dexamethasone, suggesting that this PLA2 isozyme is resistant to the inhibitory effects of glucocorticoids. Of the LxA4 and PAF, formed by sPLA2 IIA and sPLA2 -V during resolution, it is known that the former possesses suppressive effects on leukocyte functions [355] and inhibits inflammatory cell infiltrations [356] and that both compounds enhance macrophage phagocytosis of apoptotic cells [357–359]. The cPLA2 and COX-2, expressed during resolution, are responsible for the formation of PGD2 and cyclopentenone prostaglandin metabolites, both of which play an important role in mediating the resolution [348]. Finally, the same group investigated the inflammatory response in several strains of mice exhibiting the normal

Fig. 3. Possible effects of sPLA2 -IIA upregulation during sepsis. Pathogenic and protective effects, which can be seen as arrayed opposite each other and in the end decide whether in an sPLA2 -IIA upregulation during sepsis the enzyme is a positive or negative factor and whether the suppression of sPLA2 -IIA in the prevention and therapy of sepsis can be connected with beneficial effects.

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sPLA2 -IIA genotype or containing a natural mutation, resulting in an inactive gene product [352]. In this it was shown in a carrageenan-induced air pouch that the amount of inflammatory cell infiltrates was significantly greater in sPLA2 IIA-negative mice in comparison to sPLA2 -IIA-positive mice. During the early onset phase the level of inflammation was the same in both strains of mice. Although the results of this study are very impressive, it remains to be clarified, if the significant role of sPLA2 -IIA in mediating the resolution of inflammation is applicable to humans. 6. Conclusions and perspectives The current review shows that sPLA2 -IIA is a multipotent enzyme which, in addition to its pathogenic effects, may have also protective functions during inflammation. Particularly the efficient bactericidal properties of sPLA2 -IIA

Fig. 4. Schematic representation of the effects, described more closely in this work, of a locally induced sPLA2 -IIA-upregulation in the vessel wall or the sPLA2 -IIA expression as the consequence of an acute-phase-reaction for the process of atherosclerosis. As a possible pathological effect of arterial sPLA2 -IIA expression only the enhanced uptake of sPLA2 -IIA-modified lipoproteins in macrophages, resulting in foam cell formation has been illustrated. Further proatherogenic effects are described in Section 4.2.

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demonstrated in recent years put the function of sPLA2 -IIA in another light. Even though the bactericidal properties of sPLA2 -IIA have been demonstrated in vitro and in vivo cannot be uncritically attributed to its effect in humans, it is tempting to speculate that a statin therapy for patients with bacterial infections characterized by an heightened formation of IFN-␥ and IL-1␤, in comparison to patients who have not taken statins, leads to an increased expression of sPLA2 -IIA. With a statin therapy patients could be more resistant to bacterial infection, thereby explaining the possible benefits of statins in the prevention and therapy of sepsis [313–316]. Along with antibacterial characteristics the antithrombotic properties of sPLA2 -IIA have been described, such that here a further explanation of the benefits of statins could exist, in that through the induced sPLA2 -IIA expression the formation of clots is hampered. Microvascular thrombosis occurs very frequently in sepsis and septic shock connected with organ failure. In Fig. 3, the discussed effects associated with the sPLA2 -IIA upregulation during sepsis are opposed. The extent to which an expression of sPLA2 -IIA has pathogenic or protective functions with respect to atherosclerosis depends possibly on whether expression of the enzyme as the consequence of an inflammatory reaction is induced locally in the vessel wall or systemically as the result of an acute-phase-reaction. In the former case the investigations on transgenic mice speak for the notion that sPLA2 -IIA expression is connected with an increased susceptibility to atherosclerosis. By comparison, in a systemic expression the possibility exists that a protective effect grows out of this in that with inflammation the increased number of oxidatively modified lipoproteins are removed from the bloodstream via the liver and to a lesser extent via the adrenals (summarized in Fig. 4). 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