S100 proteins in atherosclerosis

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Review

S100 proteins in atherosclerosis Xuan Xiaoa,b,c,1, Chen Yangb,1, Shun-Lin Qub,1, Yi-Duo Shaoa,d, Chu-Yi Zhoua,d, Ru Chaob, ⁎ ⁎ Liang Huanga, , Chi Zhangb, a

Research Lab for Clinical & Translational Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, People’s Republic of China Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, People’s Republic of China c Departments of Clinical Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, People’s Republic of China d Departments of Stomatology, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, People’s Republic of China b

A R T I C LE I N FO

A B S T R A C T

Keywords: Atherosclerosis S100A8 S100A9 S100A12 RAGE

Atherosclerosis is an arterial disease associated with dyslipidemia, abnormal arterial calcification and oxidative stress. It has been shown that a continued chronic inflammatory state of the arterial wall contributes to the development of atherosclerosis. The inflammatory stimulation, recruitment of inflammatory cells and production of pro-inflammatory cytokines enhances vascular inflammation. Some members of the S100 proteins family bind with their receptors, such as advanced glycation end products (RAGE), scavenger receptors (CD36) and tolllike receptor 4 (TLR-4), contributing to the cellular response in atherosclerotic progression. This review summarizes the roles of S100 proteins (S100A8, S100A9 and S100A12) in the vascular inflammation, vascular calcification and vascular oxidative stress. S100 proteins are released from monocytes, smooth muscle cells and endothelial cells in response to cellular stress stimuli, and then the binding of S100 proteins to RAGE activate downstream signaling such as transcription factor kappa B (NF-κB) translocation and reactive oxygen species (ROS) production, which act as a positive feedback loop for inducing pro-inflammatory phenotype in a wide variety of cell types including endothelial cells, vascular smooth muscle cells and leukocytes. Thus, it suggests that the inhibition of S100 proteins-mediated RAGE and TLR4 activation appears to be a promising approach to treat atherosclerosis. In addition, recent study showed that serum S100A12 can predict future cardiovascular events, highlighting that S100A12 is likely to be a potential biomarker of therapeutic efficacy and disease progression in coronary heart disease. Future studies of patients with coronary heart disease may provide more evidences supporting that S100 proteins is promising drug target in the prevention and therapy of atherosclerosis.

1. Introduction According to a recent data, about 17.5 million people die of cardiovascular disease every year in the world, and cardiovascular disease remains one of the leading causes of human death [1]. Atherosclerosis is the most common pathological process in the development of cardiovascular diseases. It is now known that atherosclerosis is a chronic

inflammation of the blood vessel wall formed by the involvement of various activated immune cells and smooth muscle cells (SMC) [2]. In recent years, a variety of inflammation-related serum markers have been used to investigate their relationship to atherosclerosis [3–6]. From the relevant research results currently available, receptors for advanced glycation end products (RAGE) and toll like receptor 4 (TLR4) played an important role in many acute and chronic inflammations,

Abbreviations: SMC, smooth muscle cell; ROS, reactive oxygen species; RAGE, receptor for advanced glycation end products; AGE, advanced glycation endproducts; ACS, acute coronary syndrome; sRAGE, the soluble receptor for advanced glycation end product; Nox1, NAD(P)H oxidase 1; Rac1, ras-related C3 botulinum toxin substrate 1; CKD, chronic kidney disease; MAPK, mitogen-activated protein kinase; EF, elongation factor; TLR-4, toll like receptor 4; MRP, myeloid-related protein; Ig, immunoglobulin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; M-CSF, macrophage colony-stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; G-CSF, granulocyte colony stimulating factor; IL, interleukin; TNF, tumor necrosis factor; MMP, matrix metalloproteinase; Apo, apolipoprotein; Runx-2, runt-related tran-scription factor-2; WT, wild type; JAK2, janus kinase 2; STAT, signal transducers and activators of transcription; Qcompounds, quinoline-3-carboxamides; ERK, extracellular regulated protein kinase ⁎ Corresponding authors. E-mail addresses: [email protected] (L. Huang), [email protected] (C. Zhang). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.cca.2019.11.019 Received 18 September 2019; Received in revised form 11 November 2019; Accepted 14 November 2019 0009-8981/ © 2019 Elsevier B.V. All rights reserved.

Please cite this article as: Xuan Xiao, et al., Clinica Chimica Acta, https://doi.org/10.1016/j.cca.2019.11.019

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S100A8, S100A9 and S100A12 have mainly been implicated in the cardiovascular disease according to current findings [11,129,130]. As inflammatory factors, S100 proteins (S100A8, S100A9 and S100A12) could appear in cells and the circulating blood, and their generation is closely associated with inflammation. In neutrophil cytoplasmic proteins, S100A8/A9 accounts for about 40% and S100A12 accounts for about 5% [85,130]. This may be in favor of illustrating the main source of S100 proteins. Significantly, chronic inflammation of the vascular walls is a main trigger and driver of atherosclerosis and plaque growth. Activated endothelial cells release leukocyte adhesion molecules and chemokines, and then the infiltration of leukocytes such as macrophages, T lymphocytes and B lymphocytes into the blood vessel wall to induce blood vessels stress response [131]. On one hand, S100 proteins, which secreted from medullary cells including neutrophils and monocytes, responded to invading bacterial pathogens. On the other hand, the released S100 proteins could also act as cytokines to activate the cell surface receptor of RAGE and TLR-4. These functions contributed to mediating a series of autoimmune responses, which are also known as damage-associated molecular model patterns [132–136]. In 1992, RAGE was initially found in bovine lungs due to its combination with advanced glycation endproducts (AGEs) [137]. RAGE consists of a V-type domain, two C-type immunoglobulin (Ig)-like domains (C1 and C2), a transmembrane spanning helix and a cytoplasmic domain for signal transduction. S100A12 binds to the V-C1 domain, but the binding sites of S100A8 and S100A9 for RAGE are unclear. The research evidence indicated that the binding of S100A12 to RAGE was minimally damaged as the concentration of heparin sulfate increases, but it could affect the binding of S100A8/A9 to RAGE because of the competition between S100A8/A9 and heparin sulfate molecule [138]. In addition, glycan enrichment of RAGE resulted in a 30-fold increase in the binding capacity of S100A12 to RAGE, which is unique to S100A12 [139]. This indicates that S100A12 may be the one most likely to activate RAGE. The binding of S100A12 to RAGE initiates a signaling cascade leading to inflammatory response in vitro and in vivo, and the secretion of inflammatory mediators such as Interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α increase [134,140]. According to the current research results, we know that RAGE is the major binding receptor for S100 proteins [138,141]. When S100 proteins bind to RAGE on the cell membrane, activation of RAGE triggers the inflammatory intracellular signal transduction pathways of endothelial cells and vascular SMCs, and this will promote the secretion of pro-inflammatory cytokines such as TNF-α and IL-6, leading to acute inflammation and endothelial dysfunction [138,141]. It was found that atherosclerosis was attenuated in ApoE−/−/RAGE−/− mice compared with ApoE−/− mice [7]. Compared to the vascular endothelial cells derived from ApoE−/− mice, the expression of vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinase (MMP)-2, which contributed to the vascular inflammation by acting on pro-inflammatory cytokines, were obviously down-regulated in the vascular endothelial cells derived from ApoE−/−/RAGE−/− mice after incubation with S100 proteins [7]. Therefore, it is possible to reduce progression of atherosclerosis by blocking the activation of RAGE by using endogenous and pharmacological compounds capable of binding to RAGE-ligands. In addition, an investigation has also confirmed that S100A8/A9 may facilitate chemotaxis of macrophages and neutrophils by simulating the release of inflammatory factors (including VCAM-1) by Mac-1 [142]. In spite of lacking RAGE on the membrane of mast cells, there was evidence that S100A12 can activate mast cells by the release of histamine and certain cytokines (such as IL-6) [89]. S100A12 can boost the chemotactic activity of mast cells and monocytes via G-protein coupled receptors without RAGE [143]. It was revealed that S100A12 could also interact with scavenger receptors (including CD36) in human aortic endothelial cells and macrophages, which was associated with pathological outcomes of atherosclerosis [144,145]. Remarkably, Gprotein coupled receptors were also involved in the chemotactic effects of S100A8 on neutrophils and monocytes [56,146,147]. The

and their serum concentration changes significantly in cardiovascular diseases. RAGE and TLR-4 were primarily responsible for the transmission of released or up-regulated signals in the inflammatory response. This was proved by the mitigated atherosclerosis in apolipoprotein (Apo) E-deficient mice lacking RAGE or TLR-4 signaling [7,8]. However, RAGE might play a minor role in maintaining normal growth and development, as the lack of RAGE had a slight effect on mouse development and phenotype. Differently, the absence of TLR4 signaling leads to the growth of tumor cells in multiple organs [9]. This hints that RAGE or RAGE-mediated signaling may be an effective therapeutic target. The S100 protein family consists of 21 members that are expressed exclusively in vertebrates and exert intracellular and extracellular regulatory effects [10]. Of the S100 protein family, S100A8, S100A9 and S100A12 are closely related to cardiovascular disease. S100A8 has the ability to combine with TLR-4 and G protein coupled receptor and S100A9 was only linked with TLR-4, while S100A8/A9 (a heterodimeric complex) can interact with RAGE and scavenger receptors besides TLR-4 [11]. Moreover, S100A12 is associated with the activation of RAGE, G protein coupled receptor and scavenger receptors [11]. However, there were increasingly experimental data to prove that RAGE and TLR were closely related to the formation of atherosclerosis. As the ligands of RAGE and TLR-4, serum concentrations of S100A8, S100A9 and S100A12 are significantly elevated in acute coronary syndrome (ACS), coronary artery calcification, and cardiovascular intimal hyperplasia [12–14]. The binding of ligands including S100A8/ A9 and S100A12 to RAGE could activate endothelial cells, vascular SMCs and inflammatory intracellular signal transduction pathways inducing transcription and secretion of pro-inflammatory cytokines and cell adhesion molecules, and leading to leukocyte infiltration, aggravation of oxidative stress and vascular inflammatory response [15]. Recently, platelet-derived S100A9 has been shown to play an important role in the regulation of thrombosis [16]. This article reviews the evidence about the relationship between S100 protein (mainly S100A8, S100A9 and S100A12) and atherosclerosis. With increasing understanding of S100 protein functions, new insights and treatment strategies should emerge in the prevention of atherosclerosis. 2. The S100 proteins and vascular inflammation A first study on S100 protein was reported in 1965. This protein had the characteristic of being able to dissolve in 100% saturated ammonium sulfate solution at neutral pH, hence named “S100 protein” [17]. The members of the S100 protein family differ in structure and function (Table 1), but all contain calcium-binding protein motifs known as the elongation factor-(EF) hands. The spatial conformation of the protein changes upon binding of calcium ions to the EF-hand, allowing interaction with various target proteins and receptors, and participation in multiple functions related to cell growth and development. However, in some S100 proteins-induced events such as non-intracellular spatial signaling and high levels of calcium concentration, make their biological activity more likely to be affected by Zinc or Copper. S100A8, S100A9 and S100A12 are members of the S100 protein family and have homologous structures and functions, commonly referred to as S100/ calgranulins. There are two other names for S100A8: calgranulin A and myeloid-related Protein (MRP) 8. S100A9 also has two other names: calgranulin B and MRP14. These two proteins are often covalently combined to form the 24 kDa heterodimer S100A8/A9, also known as MRP 8/14 or calprotectin. S100A8 is the light chain in the calcium granule heterodimer (10.8 kDa), and S100A9 is the heavy chain (13.2 kDa) [18,19]. S100A12 is also known as calgranulin C or ENRAGE and CAAF1. S100A8, S100A9, S100A12 are mainly expressed in myeloid-derived cells, such as neutrophils, monocytes and dendritic cells [11,20]. The members of S100 protein family that are linked with inflammation include S100A4, S100A7, S100A13 and S100A15, but 2

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Table 1 The different functions of S100 proteins. S100 proteins

Intracellular functions

Extracellular functions 2+

-ATPase and RyR2 of

S100A1

Interact with sarcoplasmic reticulum Ca cardiomyocytes [21].

S100A2

Bind to p53 transactivation domain and potentiate p53 as a tumor-suppressing protein [24]. 1. Epithelial cell differentiation, Ca2+ -dependent hairs in the formation of the skin barrier [27]. 2. Prevent hair from oxidative damage with affluent Cys[28]. Interact with cytoskeletal proteins to promote cell migration [29].

S100A3

S100A4

S100A5 S100A6

S100A7

S100A5 expression is upregulated in bladder cancers [36] and recurrent grade I meningiomas [37], but its pathological significance is still unclear 1. Participate in cell proliferation, cytoskeletal dynamics and tumorigenesis [38,39]. 2. Interact with a calmodulin-binding protein/Siah-1 interacting protein and inhibit the interaction between heat shock proteins (Hsp70 and Hsp90) and Sgt1 or Hop to favor apoptosis in some cells [40]. 1. Be upregulated by pro-inflammatory cytokines in human breast cancer [42]. 2. Bind to c-Jun activation domain-binding protein 1 with Akt and NF-κB activiated, and promote aggressive features in breast cancer [43].

S100A8

1. Participate in myeloid cell differentiation [49]. 2. Stimulate keratinocyte differentiation by inhibiting telomerase activity [50]. 3. Suppress NADPH oxidase activation and transnitrosylate hemoglobin by Snitrosylation of S100A8 [51]. 4. Regulate transendothelial migration of neutrophils by reducing p38 mitogen-activated protein kinase (MAPK)-dependent phosphorylation of S100A9 in neutrophils [52].

S100A9

1. Eliminate S100A8-induced reduction of telomerase activity [50]. 2. Reduce microtubule polymerization and F-actin cross-linking via the S100A8/S100A9 complex [52]. 3. Restrain myeloid (dendritic cell and macrophage) differentiation and accumulation of myeloid-derived suppressor cells in pathological responses by intracellular ROS generation, thereby accelerating tumor growth [64]. 4. As a substrate of p38 MAPK, phosphorylation of MRP14 regulates exocytosis by promoting cytoskeletal reorganization [65]. Promote NADPH oxidase activation in phagocytes by interaction with p67 phoxand Rac-2 and enhance ROS levels [72].

S100A8/A9

S100A10

S100A11

Enhance the binding of certain membrane proteins(e.g. actin-binding protein AHNAK) to annexin 2 by forming ternary complex with them, which facilitates the transport of S100A10 to the plasma membrane [77,78]. 1. Suppresses cell growth by the binding to nucleolin, translocating to the nucleus, and activating the cell cycle modulator p21 WAF1/CIP1 [80]. 2. Bind to Rad54B (a DNA-dependent ATPase) participated in recombinational repair of DNA damage [81]. 3. Act on normal human keratinocytes to strengthen the generation of epidermal growth factor (EGF) family proteins, thereby stimulating cell growth [82].

Promote Ca2+ flow into cultured ventricular cardiomyocytes [22] and protein kinase A-dependent Cav1 channel currents, lengthen action potentials and enlarge action potential-induced Ca 2+ transients in neurons [23]. Implicate in chemotaxis of eosinophils and calcification of cartilage/bone [25,26]. Unknown

1. Downregulate the pro-apoptotic Bax and the angiogenesis inhibitor thrombospondin-1 genes, and facilitate production of MMPs in endothelial and tumor cells [30]. 2. Stimulate production of cytokine thereby impacting allergic inflammation [31,32]. 3. Accelerate tumor progression by collaborating with RANTES (CCL5) and interacting with EGF receptor (EGFR) ligands, thereby promoting EGFR/ ErbB2 receptor signaling and cell proliferation [33,34]. 4. Motivate cardiac myocyte growth, survival, and differentiation [35]. Unknown 1. Regulate allergic responses via inhibiting histamine that are released by mast cells [38,39]. 2. Affect RAGE-dependent survival of neuroblastoma cells by stimulating apoptosis and production of ROS through activating c-Jun NH2 terminal protein kinase [41]. 1. Involve in antimicrobial responses and innate immunity [44,45]. Lymphocytes, monocytes and granulocytes need the bond of S100A7/RAGE and Zn2+ to generate chemotactic activity, and S100A7 can cooperate with S100A15 thereby aggravating inflammatory response and promote ROS production from neutrophils [46,47]. 2. Prohibit production of amyloidogenic peptides in Alzheimer's disease [48]. 1. Mitigate inflammation response by scavenging oxidant and generating functional modifications [53–55]. S100A8 generates chemotaxis for leukocytes at picomolar concentrations according to leukocytes oxidation state [56,57], but the impact of S100A8 on leukocyte adhesion is still in controversy [56,58]. 2. Induce generation of TNF-α and IL-1β by binding to TLR-4, but this can be inhibited by S100A9 [59]. 3. Show an auto-regulatory mechanism of MMP. It can upregulate and activate MMPs and aggrecanase enzymes from chondrocytes resulting in pericellular matrix degraded through activating FcγRI and FcγRIV on macrophages by the binding to TLR-4 [59–61]. However, S100A8 is also capable of suppressing MMP activity [62]. 4. S100A8 induction may be dependent on ROS production in several cells, such as macrophages [63]. 1. Regulate leukocytes (mainly including neutrophils and macrophages) migration, adhesion and transmigration from vascular wall. [56,66,67]. 2. Mediate dystrophic calcification [54]. 3. Mitigate inflammation response by suppressing neutrophils migration and macrophages activation [68–70]. But anti-inflammatory properties are still controversial. 4. Modulate the degree of the acquired immune response by mediating costimulatory molecule, B7, expressed on antigen-presenting cells [64,71]. 1. Anti-microbial traits [73,74]. 2. Prohibit acute inflammation through binding and mediating activities of proinflammatory cytokines, and promote endothelial cell damage in vasculitis and inflammatory disease [75]. 3. Suppress growth of various normal cell types (such as macrophages, bone marrow cells, lymphocytes) and facilitate apoptosis of numerous tumor cell lines [76]. Be related to promyelocytic leukemia by promoting tPA-dependent plasmin generation [79]. 1. Prohibit fertilization by acting on cumulus cells in mice [83]. 2. Promote chondrocyte hypertrophy and matrix catabolism by binding to RAGE and activating the p38 MAPK pathway [84].

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Table 1 (continued) S100 proteins

Intracellular functions

S100A12

1. Regulate interactions between cytoskeletal elements and membranes [85]. 2. Overexpression causes several vascular smooth muscle cell (VSMC) dysfunctions in human aortic aneurysms by regulating mitochondrial function and promoting the production of proMMP2, phosphorylation and nuclear transport of Smad2 [86]. 3. Interact with Nox-1, which increases NADPH oxidase-mediated generation of peroxide, and increased ROS can upregulate multiple osteogenesisrelated genes, resulting in vessel calcification [87]. 4. Decrease chemokine secretion in activated human airway SMC thereby alleviating allergen-induced airway inflammation [88]. Affect the release of IL-1α, the activity of NF-κB and the transcription of senescence-associated secretory phenotype genes [90].

S100A13

Extracellular functions

S100A14

Modulate the p53 pathway as a cancer suppressor, and restrain the expression of matrix metalloproteinases, MMP1 and MMP9 [94,95].

S100A15

Unknown

S100A16

1. Inhibit the expression of tumor suppressor protein p53 in some tumors [99]. 2. Reduce insulin sensitivity of adipocytes [100]. 1. Bind with various target proteins, including tubulin, the microtubuleassociated τ protein, the actin-binding protein caldesmon, calponin, type III intermediate filament subunits, annexin 6 membrane-bound guanylate cyclase, the small GTPase Rac1 and Cdc42 effector IQGAP1, Src kinase, the serine/threonine protein kinase Ndr, the tumor suppressor p53, intermediates upstream of IKKβ/NF-κB, the giant phosphoprotein AHNAK/ desmoyokin, the E3 ligase hdm2, dopamine D2 receptor and the mitochondrial AAA ATPase, ATAD3A [24,101–113]. All of these are related to multiple activities including maintenance of shape, transcription, protein degradation, Ca2+ homeostasis, energy metabolism and enzyme functions. 2. Downregulate expression of dopamine D2 receptor and G protein-coupled receptor kinase2, followed by increased dopamine synthesis and decreased serotonin levels, or interact with the third cytoplasmic loop of the dopamine D2 receptor and ERK1/2 mediating the inhibition of adenylyl cyclase activity in striatal neurons [114,115] 1. Regulate adsorption of Ca2+ by acting as cytosolic Ca2+ buffers in various tissues [123]. 2. Interact with phospholipids, then the transport of S100 proteins through membranes gets promoted [124]. 1. Activate ezrin/radixin/moesin thereby promoting tumor cells transendothelial migration [125]. 2. Reduce cell adhesion through dispersing NMMHC IIA fibers, which contributes to cell migration and underlying metastasis [126] S100Z expression is downregulated in some tumors [128], but its pathological significance is still unclear.

S100B

S100G

S100P

S100Z

1. Induce pro-inflammatory cytokine generation from mast cells, which involve in recruitment of neutrophil, monocyte and lymphocyte [89]. 2. Bind to RAGE, resulting in up-regulation of osteoblastic genes, which exerts a role in promoting remodeling of atherosclerotic plaque and nodular calcification in vascular smooth muscle cells [87].

1. Benefit S100A13 intracellular translocation by RAGE binding on endothelial cells [91]. 2. Involve in the non-classical secretion of FGF-1 [92], which may be beneficial to angiogenesis [93]. Stimulate esophageal squamous cell carcinoma (ESCC) proliferation through activating ERK1/2 MAPK and NF-κB signaling pathways at low doses of extracellular S100A14, but induce apoptosis in ESCC via the activation of caspase-3, caspase-9, and poly (ADP-ribose) polymerase at high dose of extracellular S100A14 [96]. 1. Attract monocytes and granulocytes, and cooperate with S100A7 in leukocyte recruitment in vitro and in vivo [97]. 2. Against E. coli in human [98]. Unknown

1. Generate different biological effects of astrocytes and microglia depending on S100B concentration. For example, S100B has an anti-apoptotic effect when the concentration is up to a few nanomolar, while it promotes apoptosis at a micromolar dose [116–118]. 2. Neuro-inflammation is closely associated with S100B [119,120]. 3. Be beneficial to the diagnosis and treatment of Parkinson's disease [121]. 4. Regulate the proliferation of vascular smooth muscle cell through interaction between S100B and RAGE [122].

Unknown

Binding with RAGE of cancer cells, thereby regulating tumor growth, drug resistance and metastasis [127].

Unknown

arteriosclerotic vessels [142]. In summary, S100A8/A9 and S100A12 act as inflammatory mediators in vascular inflammation and atherosclerosis, possibly by activating the recruitment of RAGE receptors, CD36 and inflammatory cells such as neutrophils and macrophages, thereby accelerating the formation of atherosclerosis.

phosphorylation of interleukin-1 receptor-associated kinase-1 (IRAK-1) in monocytes could be enhanced by S100A8 binding to TLR-4, which was followed by the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and the enhanced expression of proinflammatory cytokines such as TNF-α [136]. Moreover, it was found that S100A8/A9 was also participated in the activation of scavenger receptor CD36, which strengthened inflammatory responses in endothelial cells [148]. These studies indicate that S100 proteins are also effective stimulators of acute inflammatory responses and can be independent of RAGE. More interestingly, clinical studies in patients with ACS have also confirmed that the concentration of MRP-8/14 (S100A8/ A9) heterodimer in coronary blood was associated with thrombus formation in acute coronary syndrome, and the expression of MRP8/14 was consistent with the location of Mac-1 on the surface of leukocytes and may be related to the activation of leukocytes [149]. In addition to the reduction of macrophage and neutrophil infiltration in the arteries of S100A9−/− mice, it was found that endothelial cell proliferation, inflammatory factors (such as TNF-α, MCP-1, and IL-1β) and macrophages infiltration in plaques were decreased in the absence of S100A9

3. The S100 proteins and vascular oxidative stress The balance of reactive oxygen species (ROS) production and elimination maintains the cellular redox homeostasis. Under oxidative stress in the pathogenesis of arterial diseases, the redox homeostasis is broken down by enhanced ROS production and decreased ROS elimination. The accumulation of ROS can be infiltrated in the blood and intercellular substance, leading to cell injury and dysfunction. S100 proteins participate in multiple pathways to increase intracellular ROS by binding to the RAGE or NADPH oxidase (Nox) system (mainly Nox1), upregulate the expression of vascular smooth muscle osteogenic genes, and increase vascular calcification and plaque instability [87,150]. Interestingly, transgenic mice were developed to express 4

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oxidation reaction that upregulates osteogenic genes expression in cells. Apart from that, there is evidence that hyperglycemia can promote myelopoiesis through S100A8/A9 and RAGE. Increased myeloid cells such as granulocyte macrophage progenitor cells and common myeloid progenitors can cause leukocytosis, which may be a potential mechanism for atherosclerosis [152]. Under the condition of hyperglycemia, neutrophils could produce S100A8/A9 after being stimulated by ROS, which bound to RAGE on myeloid progenitor cells, and subsequently activated the NF-κB signaling pathway to exert corresponding biological effects, including the distinct elevation of macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF) in bone marrow cells [152]. This led to leukocytosis and eventually forms a positive feedback loop, which worsens the degree of atherosclerosis. Furthermore, atherosclerotic lesion regression emerges both in RAGE−/− mice and mice with low blood glucose levels [152]. This phenomenon further validates the relationship among hyperglycemia, S100A8/A9, RAGE and atherosclerosis. Nowadays, it has been accepted widely that diabetes is a type of metabolic disease characterized by hyperglycemia and is caused by decreased insulin sensitivity and/or impaired insulin secretion. [154]. Most of the deaths and morbidity of diabetic patients are caused by long-term microvascular and macrovascular complications of chronic hyperglycemia. Generally, macrovascular complications occur mostly in patients with cardiovascular, cerebrovascular and peripheral arterial diseases, most of which incorporate atherosclerosis [155]. The above discussion indicates that oxidative stress responses and S100 proteins are closely related and inextricably linked pathophysiological processes in atherosclerosis (as shown in Figs. 1 and 2) [156]. It has been revealed that hyperglycemia can cause an increase in the production of reactive oxygen species (ROS) in human endothelial cells, while overexpression of S100A8 and RAGE is also found in aortic endothelial cells of diabetic mice [157]. Similarly, levels of circulating S100A8/A9 in patients with Type 2 diabetes elevates, which indicates that S100A8/A9 can be used as an inflammatory marker of glucose tolerance impairment [158]. A survey of 664 healthy middle-aged people (63–68 years old) with no history of cardiovascular disease showed that blood S100A8/A9 concentrations is positively correlated with the number of neutrophil, and is closely related to acute coronary

human S100A12 in vascular SMCs for the lack of S100A12 in wild type (WT) mice, which provided an animal model to explore the existence of any association between S100 proteins and atherosclerosis. It was found that S100A12 can aggravate the degree of atherosclerosis by using transgenic mice expressing human S100A12 in SMCs [129]. It was also observed that the transgenic mice expressing human S100A12 exhibited increased expression of osteogenic genes such as Runx-2 in SMCs, which might be a underlying mechanism responsible for the pathological vascular remodeling [151]. In addition, a previous study performed by using arterial SMCs derived from S100A12 transgenic mice stated that the increased amount of intracellular ROS and the elevated expression of many osteogenic genes can even occur earlier than the obvious vascular calcification [87]. S100A12 could accelerate the phenotype of SMCs from contraction to synthesis, and the increase of oxidative stress further stimulated the generation of MMP2/9, IL-6 and Smad2, which ultimately led to the formation of thoracic aortic aneurysm in S100A12 transgenic mice [86]. It was found the soluble receptor for advanced glycation end product (sRAGE) competitively bound to the binding site of RAGE and S100A12 in the simulated hyperoxidative inflammatory environment, and the intracellular osteogenic gene expression was obviously down-regulated, calcium content was reduced by 30%, but no osteogenic gene expression was found in cells which showed no Nox1 expression [87,152]. These findings strongly demonstrate the importance of RAGE and Nox in S100A12mediated oxidative damage. Nox1 activation was regulated by cytoplasmic cofactors, including ras-related C3 botulinum toxin substrate 1 (Rac1), guanosine triphosphates (GTPases) and Nox activator protein 1. RAGE binding to S100A12 leads to the activation of Rac1, which has roles in activating NADPH oxidases and enhancing oxidative stress (as shown in Fig. 1) [150]. Moreover, the molecular structures of S100A8 and S100A9 are more susceptible than S100A12 when oxidative stress is enhanced [68]. This will facilitate the recruitment of neutrophils and form a positive feedback effect, which will further aggravate oxidative stress. However, it is also suggested that large amounts of S100A8 and S100A9 could protect against oxidative damage in atherosclerotic plaque by scavenging oxidants at inflammatory sites [153]. ROS is closely related to S100 proteins-induced atherosclerosis. As an upstream molecule that provokes the production of ROS, S100A12 binds to the cell surface receptor-RAGE, which results in enhanced

Fig. 1. The production of ROS caused by S100A12 and hyperglycemia. S100A12 can promote intracellular ROS production in two ways, either by binding to RAGE or directly acting on the Nox system. S100A12 in combination with RAGE activates Rac1, causing the Nox system to be triggered. Hyperglycemia can also directly lead to high levels of intracellular ROS. Increased ROS can cause activation of Runx2, MMP 2/9, Smad2 and IL-6, thereby inducing a series of changes that promote the development of atherosclerosis, including osteogenic differentiation of vascular smooth muscle cells, degradation of extracellular matrix, apoptosis and inflammation.

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Fig. 2. High glucose-mediated S100A8/A9-RAGE pathway leads to positive feedback regulation of inflammatory cells. Under the condition of hyperglycemia, S100A8/A9, which released from neutrophils after being stimulated by ROS, binds to RAGE on myeloid progenitor cells and activates the NF-κB signaling pathway to exert corresponding biological effects, including the distinct elevation of M-CSF, GM-CSF, and G-CSF in bone marrow cells. The augmentations of hematopoietic cytokines and S100A8/A9 aggrandize the number of inflammatory cells (neutrophils and monocytes) and their infiltration in vascular wall. This reciprocates to form a positive feedback effect.

osteogenic genes such as runt-related transcription factor-2 (Runx-2) in SMCs [151]. In fact, aortic tissue or primary aortic SMCs derived from young S100A12 transgenic mice showed increased ROS and upregulation of many bone regulatory genes even before significant vascular calcification occurs [87]. A group of proteins that are in the vesicles of the matrix-annexin may also promote vascular calcification by the binding of S100 protein to annexin [167]. Matrix vesicles that are released from SMCs, macrophages, bone cells and other cells can accumulate in the extracellular matrix and facilitate the formation of minerals in the extracellular matrix [168–170]. In transgenic S100A12 hyperlipidemia mice, the expression of osteogenic genes such as Runx-2, bone morphogenetic protein-2, and osteocalcin were up-regulated [87]. In addition, compared with ApoE−/− mice, the areas of atherosclerotic plaques were enlarged in overexpressing S100A12 ApoE−/− mice, and calcified plaques were significantly increased [87]. Interestingly, no obvious calcified nodules were found in the aortic blood vessels expressing S100A12 cultured in the absence of inflammatory cytokine broth [87]. These results demonstrated that S100A12 required an inflammatory environment to promote vascular calcification and atherosclerosis, and this theory has also been validated in a mouse model of CKD. S100A12 binds and activates RAGE to accelerate vascular calcification, and this process is significantly enhanced in the presence of hyperlipidemia and oxidative stress [171]. Transgenic S100A12 mice with normal plasma lipid concentrations are not fully vascularized with aging [87]. Aortic SMCs were less calcified by preconditioning with soluble RAGE (a binding region of RAGE, limiting S100A12 and other ligands into RAGE) for aortic SMCs and abolishing Nox1 (the main component of NADPH oxidase of SMCs) [171]. These findings suggest that activation of signaling pathways associated with RAGE and Nox1 requires a suitable cellular environment. Clinical data demonstrated that the elevation of S100A12 in plasma of patients with stage 5 chronic kidney disease escalated atherosclerosis and was positively associated with complications such as diabetes, cardiovascular disease, and mortality [172]. It is noticeable that S100A12, which affects the progression of atherosclerosis, only expressed in vascular smooth muscle cells in ApoE−/− mice, whereas S100A12 and S100A8/A9 in human blood circulation are mainly derived from the release of inflammatory cells such as

events and cardiovascular death [159]. Besides, serum S100A12 levels are also independent factors affecting the severity of coronary heart disease in patients with Type 2 diabetes [160]. More interestingly, it was found that the interaction of S100B with RAGE stimulate the generation of ROS, proliferation of SMC and phosphorylation of janus kinase 2 (JAK2) tyrosine by evoking phospholipase D (PLD)2 [122]. Angiotensin II can promote proliferation of vascular SMC via boosting signal transduction in hyperglycemia conditions after JAK2 activated [122]. Furthermore, interaction between S100B and RAGE causes translocation of c-Src (a member of tyrosine protein kinase) and activation of Rac1, which contribute to generation of ROS, migration of cells and remodeling of vascular walls [161]. Taken together, these findings imply that hyperglycemia may facilitate atherosclerosis by promoting a positive feedback loop between S100 proteins and ROS. This information can help rationalize therapeutic targets for hyperglycemia, myelopoiesis and atherosclerotic signaling pathways modulated by S100 proteins and RAGE. However, a more detailed connection between S100A12 and hyperglycemia still requires further experimental evidence to prove.

4. The S100 proteins and vascular calcification Vascular calcification is a common pathological featured in many chronic diseases such as atherosclerosis, diabetes, and chronic kidney disease (CKD). It is both one of the important signs of atherosclerosis and the inevitable result of atherosclerosis. While the previous studies addressed that vascular calcification was caused by the passive deposition of calcium salt crystals in atherosclerotic plaques, new insight is widely accepted that atherosclerotic calcification is similar to arterial calcification, and even resembles bone formation in many aspects [162–165]. It has been found that smooth muscle cells gradually appear to have a chondrocyte-like phenotype and an increase in the expression of bone-forming proteins in the calcified lesions, which prompt that the calcification of atherosclerotic plaque may be related to changes in smooth muscle cell phenotype [166]. The vascular smooth muscle cells have phenotypic transition to osteoblast-like cells during vascular calcification. One of the mechanisms involved in vascular calcification is that S100A12-induced oxidative stress increases the expression of 6

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Fig. 3. S100A8/A9 promotes vascular endothelial cell dysfunction and apoptosis. Hyperglycemia activates PI3K and PKC pathways to up-regulate the expression of S100A8 and S100A9. High expression of S100A8/A9 in endothelial cells causes cell apoptosis. When vascular inflammation or cell damage occurs, S100A8/A9 released from inflammatory cells (neutrophils, macrophages) binds to RAGE and TLR-4 receptors on the surface of vascular endothelial cells. The dysfunction of endothelial cells eventually becomes inevitable when the combination of ligand-receptor activates MAPK subtypes downstream signaling pathway including p38MAPK, ERK1/2, JNK1/2, which lead to cytoskeleton disorganized and intercellular junctional proteins redistributed. And the elevated S100A8/A9 decreases the expression of anti-apoptotic protein Bcl-2 in endothelial cells, up-regulates the caspase-9 and the downstream product caspase-3, and promotes apoptosis. The degree of atherosclerosis gets worse and worse.

may have the potential to attenuate or even terminate S100-mediated promotion of atherosclerosis. What's more, the discovery of the relationship between CD36 and S100 proteins may provide an emerging therapeutic direction for atherosclerosis. It was found that CD36 was required for a S100A9dependent pathway of thrombosis [16]. This indicates that targeting S100A9 may also be a potential target for treating atherothrombotic disorders, including myocardial infaction and stroke. In addition, it was revealed that the anti-CD36 antibody can prohibit the binding of S100A12 to CD36 [145]. S100A12 upregulates CD36 expression and recruits CD36 to the cell membrane, and is able to induce more CD36 expression in RAGE-positive cells than that in RAGE-deficient cells [145]. However, the mechanism of atherosclerosis plague formation between S100A12 and CD36 remains to be further studied. As an alternative to conservative treatment, interventional therapy has the characteristics of small trauma, high feasibility, wide beneficiary population and exact effects. It is also one of the main methods for the treatment of coronary atherosclerosis. After coronary interventional treatment, the key to preventing restenosis is stent endothelialization. The rate of stenting restenosis in patients with diabetes was higher than that of non-diabetic patients [179]. A significant restenosis could also be observed 14 days after carotid stent implantation in the diabetic mice [179]. The gene sequence analysis of vascular tissue showed that the S100A8 and S100A9 genes were upregulated only in endothelial cells, and the endothelial cells with high expression of S100A8/A9 had the ability to promote apoptosis and reduce migration [179]. The effects of S100A8/A9 on hindering the endothelialization of the implant are substantially consistent with the endothelial cells disfunction cultured in the presence of high glucose (as shown in Fig. 3) [179]. Furthermore, coronary artery bypass grafting provides a new way for the treatment of atherosclerosis. The autologous great saphenous vein, which is often used as a vascular bridge, exhibits the loss in endothelial barrier integrity, the infiltration of immune cells and the increase of immune-regulatory factors that cause smooth muscle cells to migrate to the vascular intima resulting in restenosis following coronary artery bypass graft surgery [180]. Experiments have shown that exogenous S100A8/A9 could disrupt endothelial barrier integrity and induce endothelial cell apoptosis through Bcl-2/caspase-9/caspase-3

macrophages and neutrophils. In the clinical control study of patients with coronary heart disease, the serum levels of S100A12 in patients with coronary heart disease were significantly higher than those in the control group and positively correlated with C-reactive proteins [173]. After observation of percutaneous coronary intervention for patients with stable coronary artery disease, it was found that the concentration of serum S100A12 in the coronary sinus was higher than that in the aortic root, indicating that S100A12 was released from the ruptured plaque during treatment [173]. This means that in situ expression of S100A12 in vascular SMCs has a greater effect on vascular calcification than S100A12 released from myeloid cells. 5. The S100 proteins and the treatment of atherosclerosis S100 proteins have been recognized as potential therapeutic targets due to their relationship to chronic inflammation. It was found that atherosclerosis was alleviated after S100A9 [142] or RAGE [7] gene resection in the atherosclerosis-susceptible ApoE−/− mice. Quinoline3-carboxamides (Q-compounds), which have been available for more than 30 years, have been found to reduce autoimmune and inflammatory diseases in a variety of animal models and to retain innate immunity relatively [174–177]. So far, their exact mechanism of action is still under investigation. Remarkably, it was found that six different Q-compounds including ABR-215757 have high affinity for S100A9 in peripheral blood mononuclear cells and could be used to reduce S100A9 binding to TLR4 and RAGE [176]. The anti-inflammatory effects of ABR-215757 were tested in mice treated with lipopolysaccharide, and it was observed that the inhibitory effect of ABR215757 on TNF-α production in mice was similar to that in mice treated with monoclonal antibodies to S100A9. This result indicates that S100A9 may be a molecular target of Q-compounds [178]. In addition, ABR-215757 can combine with S100A12 in vitro, and atherosclerosis was attenuated in S100A12 transgenic mice after treated with ABR215757 [138]. However, Apo E−/− mice were less affected after treated with ABR-215757, and the researchers found no significant changes in aortic root atherosclerosis and this may be related to the lack of S100A12 in Apo E−/− mice [129]. Thus, a remarkable characteristic of ABR-215757 is that it binds to S100A12. These results indicate that S100A12 can be used as a target for drug therapy, and ABR-215757 7

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University of South China (2017XQD29), Hunan Provincial College Students Research Study and Innovative Experiment Project (2018-470, 2019-2261).

death pathway [75]. The excessive phosphorylation of p38 MAPK, extracellular regulated protein kinase (ERK1/2) and JNK1/2 resulting from S100A8/A9 binding to TLR-4 and RAGE were associated with vascular endothelial cells injury, which lead to cytoskeleton disorganized and intercellular junctional proteins redistributed [181]. What’s more, the neointimal hyperplasia in vein graft is also the main cause of restenosis after revascularization [182]. Comfortingly, it was found recently that S100A6 could modulate cell cycle activity of endothelial cell, and cell cycle entry could be prohibited by signal transducers and activators of transcription (STAT), a family of latent cytoplasmic transcription factors [183–186]. Inhibition of cell cycle entry is associated with the activation of STAT downstream effector interferoninduced transmembrane protein 1 (IFITM1), which results in up-regulation of p53/p21 [187]. S100A6 could suppress antiproliferative STAT1/IFITM1 signaling to contribute to reendothelialization though promoting the expression of protein inhibitors of activated STAT1 (PIAS1) in impaired vessels [188]. Interestingly, the S100 proteins can also be used as predictors of some vascular diseases. The levels of S100A12 and soluble RAGE are associated with cardiovascular disease risk. The previous studies have shown that serum S100A12 can be used as an independent predictor to determine elevated levels of glycated hemoglobin [189,190]. S100 proteins can also be used as biomarkers of obesity. By investigating non-diabetic obese subjects, S100A8/A9 serum levels were correlated with body mass index [191]. Serum S100A8/A9 levels increased in obesity and obesity-associated type 2 diabetes (T2D), but decreased after these obese subjects got weight loss by Roux-en-Y gastric bypass (RYGB) [192]. Additionally, serum S100A8/A9 concentration could be used as a predictor of recurrence of cardiovascular events [193], while serum S100A12 levels could predict the presence and adverse outcomes of cardiovascular disease [194,195]. The Rotterdam study confirmed that S100A12 was the only inflammatory biomarker closely related to coronary heart disease [196]. These experimental results indicate that S100 proteins play important roles in predicting future cardiovascular events and can be used to guide disease prevention.

References [1] S. Mendis, S. Davis, B. Norrving, Organizational update: the world health organization global status report on noncommunicable diseases 2014; one more landmark step in the combat against stroke and vascular disease, Stroke 46 (5) (2015) e121–e122. [2] P. Libby, Inflammation in atherosclerosis, Arterioscler. Thromb. Vasc. Biol. 32 (9) (2012) 2045–2051. [3] M. Kavousi, S. Elias-Smale, J.H. Rutten, M.J. Leening, R. Vliegenthart, G.C. Verwoert, G.P. Krestin, M. Oudkerk, M.P. de Maat, F.W. Leebeek, Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study, Ann. Intern. Med. 156 (6) (2012) 438–444. [4] B.J. Jefferis, O. Papacosta, C.G. Owen, S.G. Wannamethee, S.E. Humphries, M. Woodward, L.T. Lennon, A. Thomson, P. Welsh, A. Rumley, Interleukin 18 and coronary heart disease: prospective study and systematic review, Atherosclerosis 217 (1) (2011) 227–233. [5] J. Danesh, J.G. Wheeler, G.M. Hirschfield, S. Eda, G. Eiriksdottir, A. Rumley, G.D. Lowe, M.B. Pepys, V. Gudnason, C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease, N. Engl. J. Med. 350 (14) (2004) 1387–1397. [6] I.R.G.C.E.R.F. Collaboration, Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies, The Lancet 379(9822) (2012) 1205-1213. [7] E. Harja, D.-X. Bu, B.I. Hudson, J.S. Chang, X. Shen, K. Hallam, A.Z. Kalea, Y. Lu, R.H. Rosario, S. Oruganti, Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE–/–mice, J. Clin. Investig. 118 (1) (2008) 183–194. [8] H. Björkbacka, V.V. Kunjathoor, K.J. Moore, S. Koehn, C.M. Ordija, M.A. Lee, T. Means, K. Halmen, A.D. Luster, D.T. Golenbock, Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways, Nat. Med. 10 (4) (2004) 416. [9] S. Rakoff-Nahoum, R. Medzhitov, Toll-like receptors and cancer, Nat. Rev. Cancer 9 (1) (2009) 57. [10] D.B. Zimmer, J.O. Eubanks, D. Ramakrishnan, M.F. Criscitiello, Evolution of the S100 family of calcium sensor proteins, Cell Calcium 53 (3) (2013) 170–179. [11] R. Donato, B.R. Cannon, G. Sorci, F. Riuzzi, K. Hsu, D.J. Weber, C.L. Geczy, Functions of S100 proteins, Curr. Mole. Med. 13 (1) (2013) 24–57. [12] Z. Buyukterzi, U. Can, S. Alpaydin, A. Guzelant, S. Karaarslan, D. Kocyigit, K.M. Gurses, Enhanced S100A9 and S100A12 expression in acute coronary syndrome, Biomark. Med. 11 (3) (2017) 229–237. [13] Y.-N. Wang, Y. Sun, Y. Wang, Y.-L. Jia, Serum S100A12 and progression of coronary artery calcification over 4 years in hemodialysis patients, Am. J. Nephrol. 42 (1) (2015) 4–13. [14] A. Hirata, K. Kishida, H. Nakatsuji, A. Hiuge-Shimizu, T. Funahashi, I. Shimomura, High serum S100A8/A9 levels and high cardiovascular complication rate in type 2 diabetics with ultrasonographic low carotid plaque density, Diabetes Res. Clin. Pract. 97 (1) (2012) 82–90. [15] P. Leurs, B. Lindholm, The AGE–RAGE pathway and its relation to cardiovascular disease in patients with chronic kidney disease, Arch. Med. Res. 44 (8) (2013) 601–610. [16] Y. Wang, C. Fang, H. Gao, M.L. Bilodeau, Z. Zhang, K. Croce, S. Liu, T. Morooka, M. Sakuma, K. Nakajima, Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis, J. Clin. Investig. 124 (5) (2014) 2160–2171. [17] B.W. Moore, A soluble protein characteristic of the nervous system, Biochem. Biophys. Res. Commun. 19 (6) (1965) 739–744. [18] R.S. Bhardwaj, C. Zotz, J. Roth, M. Goebeler, K. Mahnke, M. Falk, G. MeinardusHager, C. Sorg, G. Zwadlo-Klarwasser, The calcium-binding proteins MRP8 and MRP14 form a membrane-associated heterodimer in a subset of monocytes/macrophages present in acute but absent in chronic inflammatory lesions, Eur. J. Immunol. 22 (7) (1992) 1891–1897. [19] M.J. Hunter, W.J. Chazin, High level expression and dimer characterization of the S100 EF-hand proteins, migration inhibitory factor-related proteins 8 and 14, J. Biol. Chem. 273 (20) (1998) 12427–12435. [20] M.A.H. Bowman, A.M. Schmidt, S100/calgranulins EN-RAGEing the blood vessels: implications for inflammatory responses and atherosclerosis, Am. J. Cardiovasc. Dis. 1 (1) (2011) 92. [21] D. Rohde, J. Ritterhoff, M. Voelkers, H.A. Katus, T.G. Parker, P. Most, S100A1: a multifaceted therapeutic target in cardiovascular disease, J. Cardiovasc. Translat. Res. 3 (5) (2010) 525–537. [22] M. Reppel, P. Sasse, R. Piekorz, M. Tang, W. Roell, Y. Duan, A. Kletke, J. Hescheler, B. Nürnberg, B.K. Fleischmann, S100A1 enhances the L-type Ca2+ current in embryonic mouse and neonatal rat ventricular cardiomyocytes, J. Biol. Chem. 280 (43) (2005) 36019–36028. [23] E.O. Hernández-Ochoa, B.L. Prosser, N.T. Wright, M. Contreras, D.J. Weber, M.F. Schneider, Augmentation of Cav1 channel current and action potential duration after uptake of S100A1 in sympathetic ganglion neurons, Am. J. Physiol.Cell Physiol. 297 (4) (2009) C955–C970. [24] J. van Dieck, D.P. Teufel, A.M. Jaulent, M.R. Fernandez-Fernandez, T.J. Rutherford, A. Wyslouch-Cieszynska, A.R. Fersht, Posttranslational modifications affect the interaction of S100 proteins with tumor suppressor p53, J.

6. Conclusion A large number of experimental data show that S100 proteins are not only inflammatory markers, but also participants of atherosclerosis, which is of great value in the future research of atherosclerotic diseases. The definitive evidence is scanty to show that S100 proteins can act as therapeutic targets in human atherosclerosis because of their association with other inflammatory mechanisms and lack of specifical targets in anticipative clinical trials. The biological characteristics and regulation mechanism of S100 proteins in the atherosclerotic process deserve to be further explored. Declaration of Competing Interest All authors declare that no conflict of interest exists. Acknowledgments Not applicable. Funding This work was supported by National Natural Science Foundation of China (81100106, 81100212, 81670424), Hunan Provincial Natural Science Foundation of China (2018JJ2345), Hunan Provincial Innovation Foundation for Postgraduate (CX2018B617), International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province (2018WK4031), Scientific Research Foundation for doctor of University of South China (2012XQD37, 2017XQD04), and the Scientific Research Foundation for the Returned Overseas Scholars of 8

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Mol. Biol. 394 (5) (2009) 922–930. [25] T. Komada, R. Araki, K. Nakatani, I. Yada, M. Naka, T. Tanaka, Novel specific chemotactic receptor for S100L protein on guinea pig eosinophils, Biochem. Biophys. Res. Commun. 220 (3) (1996) 871–874. [26] N. Balmain, F. Moutahir, C. Heizmann, M. Lieberherr, Immunolocalization of S100A2 calcium-binding protein in cartilage and bone cells, Cell. Mole. Biol. (Noisy-le-Grand, France) 49 (4) (2003) 485–486. [27] K. Kizawa, H. Takahara, H. Troxler, P. Kleinert, U. Mochida, C.W. Heizmann, Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer A putative Ca2+ modulator matures human hair cuticle, J. Biol. Chem. 283 (8) (2008) 5004–5013. [28] K. Kizawa, T. Inoue, M. Yamaguchi, P. Kleinert, H. Troxler, C.W. Heizmann, Y. Iwamoto, Dissimilar effect of perming and bleaching treatments on cuticles: advanced hair damage model based on elution and oxidation of S100A3 protein, Int. J. Cosmet. Sci. 27 (6) (2005) 355. [29] T.M. Ismail, D.G. Fernig, P.S. Rudland, C.J. Terry, G. Wang, R. Barraclough, The basic C-terminal amino acids of calcium-binding protein S100A4 promote metastasis, Carcinogenesis 29 (12) (2008) 2259–2266. [30] B. Schmidt-Hansen, D. Örnås, M. Grigorian, J. Klingelhöfer, E. Tulchinsky, E. Lukanidin, N. Ambartsumian, Extracellular S100A4 (mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity, Oncogene 23 (32) (2004) 5487. [31] B. Grum-Schwensen, J. Klingelhöfer, M. Grigorian, K. Almholt, B.S. Nielsen, E. Lukanidin, N. Ambartsumian, Lung metastasis fails in MMTV-PyMT oncomice lacking S100A4 due to a T-cell deficiency in primary tumors, Cancer Res. 70 (3) (2010) 936–947. [32] K. Takenaga, Y. Nakamura, S. Sakiyama, Expression of a calcium binding protein pEL98 (mts1) during differentiation of human promyelocytic leukemia HL-60 cells, Biochem. Biophys. Res. Commun. 202 (1) (1994) 94–101. [33] B. Forst, M.T. Hansen, J. Klingelhöfer, H.D. Møller, G.H. Nielsen, B. GrumSchwensen, N. Ambartsumian, E. Lukanidin, M. Grigorian, Metastasis-inducing S100A4 and RANTES cooperate in promoting tumor progression in mice, PLoS ONE 5 (4) (2010) e10374. [34] J. Klingelhöfer, H.D. Møller, E.U. Sumer, C.H. Berg, M. Poulsen, D. Kiryushko, V. Soroka, N. Ambartsumian, M. Grigorian, E.M. Lukanidin, Epidermal growth factor receptor ligands as new extracellular targets for the metastasis-promoting S100A4 protein, FEBS J. 276 (20) (2009) 5936–5948. [35] M. Schneider, S. Kostin, C.C. Strøm, M. Aplin, S. Lyngbæk, J. Theilade, M. Grigorian, C.B. Andersen, E. Lukanidin, J. Lerche Hansen, S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes, Cardiovasc. Res. 75 (1) (2007) 40–50. [36] R. Yao, A. Lopez-Beltran, G.T. Maclennan, R. Montironi, J.N. Eble, L. Cheng, Expression of S100 protein family members in the pathogenesis of bladder tumors, Anticancer Res. 27 (5A) (2007) 3051–3058. [37] S. Hancq, I. Salmon, J. Brotchi, O. De Witte, H.J. Gabius, C.W. Heizmann, R. Kiss, C. Decaestecker, S100A5: a marker of recurrence in WHO grade I meningiomas, Neuropathol. Appl. Neurobiol. 30 (2) (2004) 178–187. [38] W. Leśniak, Ł.P. Słomnicki, A. Filipek, S100A6–new facts and features, Biochem. Biophys. Res. Commun. 390 (4) (2009) 1087–1092. [39] S. Tyagi, J. George, R. Singh, K. Bhui, Y. Shukla, Neoplastic alterations induced in mammalian skin following mancozeb exposure using in vivo and in vitro models, OMICS 15 (3) (2011) 155–167. [40] Ł.P. Słomnicki, B. Nawrot, W. Leśniak, S100A6 binds p53 and affects its activity, Int. J. Biochem. Cell Biol. 41 (4) (2009) 784–790. [41] E. Leclerc, G. Fritz, M. Weibel, C.W. Heizmann, A. Galichet, S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains, J. Biol. Chem. 282 (43) (2007) 31317–31331. [42] N. West, P. Watson, S100A7 (psoriasin) is induced by the proinflammatory cytokines oncostatin-M and interleukin-6 in human breast cancer, Oncogene 29 (14) (2010) 2083. [43] E.D. Emberley, Y. Niu, L. Curtis, S. Troup, S.K. Mandal, J.N. Myers, S.B. Gibson, L.C. Murphy, P.H. Watson, The S100A7-c-Jun activation domain binding protein 1 pathway enhances prosurvival pathways in breast cancer, Cancer Res. 65 (13) (2005) 5696–5702. [44] R. Gläser, J. Harder, H. Lange, J. Bartels, E. Christophers, J.-M. Schröder, Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection, Nat. Immunol. 6 (1) (2005) 57. [45] K.C. Lee, R.L. Eckert, S100A7 (Psoriasin)–mechanism of antibacterial action in wounds, J. Invest. Dermatol. 127 (4) (2007) 945–957. [46] R. Wolf, O.Z. Howard, H.-F. Dong, C. Voscopoulos, K. Boeshans, J. Winston, R. Divi, M. Gunsior, P. Goldsmith, B. Ahvazi, Chemotactic activity of S100A7 (Psoriasin) is mediated by the receptor for advanced glycation end products and potentiates inflammation with highly homologous but functionally distinct S100A15, J. Immunol. 181 (2) (2008) 1499–1506. [47] Y. Zheng, F. Niyonsaba, H. Ushio, S. Ikeda, I. Nagaoka, K. Okumura, H. Ogawa, Microbicidal protein psoriasin is a multifunctional modulator of neutrophil activation, Immunology 124 (3) (2008) 357–367. [48] W. Qin, L. Ho, J. Wang, E. Peskind, G.M. Pasinetti, S100A7, a novel Alzheimer's disease biomarker with non-amyloidogenic α-secretase activity acts via selective promotion of ADAM-10, PLoS ONE 4 (1) (2009) e4183. [49] E. Lagasse, I. Weissman, Mouse MRP8 and MRP14, two intracellular calciumbinding proteins associated with the development of the myeloid lineage, Blood 79 (8) (1992) 1907–1915. [50] S. Rosenberger, I.S. Thorey, S. Werner, P. Boukamp, A novel regulator of telomerase S100A8 mediates differentiation-dependent and calcium-induced

[51]

[52]

[53] [54]

[55]

[56]

[57] [58] [59]

[60]

[61]

[62] [63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

9

inhibition of telomerase activity in the human epidermal keratinocyte line HaCaT, J. Biol. Chem. 282 (9) (2007) 6126–6135. S.Y. Lim, M. Raftery, H. Cai, K. Hsu, W.X. Yan, H.-L. Hseih, R.N. Watts, D. Richardson, S. Thomas, M. Perry, S-nitrosylated S100A8: novel anti-inflammatory properties, J. Immunol. 181 (8) (2008) 5627–5636. T. Vogl, S. Ludwig, M. Goebeler, A. Strey, I.S. Thorey, R. Reichelt, D. Foell, V. Gerke, M.P. Manitz, W. Nacken, MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes, Blood 104 (13) (2004) 4260–4268. H. Sroussi, J. Berline, P. Dazin, P. Green, J. Palefsky, S100A8 triggers oxidationsensitive repulsion of neutrophils, J. Dent. Res. 85 (9) (2006) 829–833. M.M. McCormick, F. Rahimi, Y.V. Bobryshev, K. Gaus, H. Zreiqat, H. Cai, R.S. Lord, C.L. Geczy, S100A8 and S100A9 in human arterial wall implications for atherogenesis, J. Biol. Chem. 280 (50) (2005) 41521–41529. J. Zhao, I. Endoh, K. Hsu, N. Tedla, Y. Endoh, C.L. Geczy, S100A8 modulates mast cell function and suppresses eosinophil migration in acute asthma, Antioxid. Redox Signal. 14 (9) (2011) 1589–1600. C. Ryckman, K. Vandal, P. Rouleau, M. Talbot, P.A. Tessier, Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion, J. Immunol. 170 (6) (2003) 3233–3242. J. Goyette, C.L. Geczy, Inflammation-associated S100 proteins: new mechanisms that regulate function, Amino Acids 41 (4) (2011) 821–842. R.A. Newton, N. Hogg, The human S100 protein MRP-14 is a novel activator of the β2 integrin Mac-1 on neutrophils, J. Immunol. 160 (3) (1998) 1427–1435. P.L. van Lent, L.C. Grevers, R. Schelbergen, A. Blom, J. Geurts, A. Sloetjes, T. Vogl, J. Roth, W.B. van den Berg, S100A8 causes a shift toward expression of activatory Fcγ receptors on macrophages via toll-like receptor 4 and regulates Fcγ receptor expression in synovium during chronic experimental arthritis, Arthritis Rheum. 62 (11) (2010) 3353–3364. P. van Lent, L. Grevers, A. Blom, O. Arntz, F. van de Loo, P. Van der Kraan, S. Abdollahi-Roodsaz, G. Srikrishna, H. Freeze, A. Sloetjes, Stimulation of chondrocyte-mediated cartilage destruction by S100A8 in experimental murine arthritis, Arthr. Rheum.: Offic. J. Am. College Rheumatol. 58 (12) (2008) 3776–3787. N. Steinckwich, V. Schenten, C. Melchior, S. Bréchard, E.J. Tschirhart, An essential role of STIM1, Orai1, and S100A8–A9 proteins for Ca2+ signaling and FcγRmediated phagosomal oxidative activity, J. Immunol. 186 (4) (2011) 2182–2191. B. Isaksen, M. Fagerhol, Calprotectin inhibits matrix metalloproteinases by sequestration of zinc, Mole. Pathol. 54 (5) (2001) 289. M.A. Grimbaldeston, C.L. Geczy, N. Tedla, J.J. Finlay-Jones, P.H. Hart, S100A8 induction in keratinocytes by ultraviolet A irradiation is dependent on reactive oxygen intermediates, J. Invest. Dermatol. 121 (5) (2003) 1168–1174. P. Cheng, C.A. Corzo, N. Luetteke, B. Yu, S. Nagaraj, M.M. Bui, M. Ortiz, W. Nacken, C. Sorg, T. Vogl, Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein, J. Exp. Med. 205 (10) (2008) 2235–2249. G. Lominadze, M.J. Rane, M. Merchant, J. Cai, R.A. Ward, K.R. McLeish, Myeloidrelated protein-14 is a p38 MAPK substrate in human neutrophils, J. Immunol. 174 (11) (2005) 7257–7267. J.C. Simard, D. Girard, P.A. Tessier, Induction of neutrophil degranulation by S100A9 via a MAPK-dependent mechanism, J. Leukoc. Biol. 87 (5) (2010) 905–914. K. Sunahori, M. Yamamura, J. Yamana, K. Takasugi, M. Kawashima, H. Yamamoto, W.J. Chazin, Y. Nakatani, S. Yui, H. Makino, The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis, Arthr. Res. Therapy 8 (3) (2006) R69. H.Y. Sroussi, J. Berline, J.M. Palefsky, Oxidation of methionine 63 and 83 regulates the effect of S100A9 on the migration of neutrophils in vitro, J. Leukoc. Biol. 81 (3) (2007) 818–824. R.L. Pagano, S.C. Sampaio, M.A. Juliano, L. Juliano, R. Giorgi, Involvement of proteinase-activated receptors 1 and 2 in spreading and phagocytosis by murine adherent peritoneal cells: modulation by the C-terminal of S100A9 protein, Eur. J. Pharmacol. 628 (1–3) (2010) 240–246. B. De Lorenzo, L. Godoy, R.N. Brito, R. Pagano, M. Amorim-Dias, D. Grosso, J. Lopes, M. Mariano, Macrophage suppression following phagocytosis of apoptotic neutrophils is mediated by the S100A9 calcium-binding protein, Immunobiology 215 (5) (2010) 341–347. K. Shimizu, P. Libby, V.Z. Rocha, E.J. Folco, R. Shubiki, N. Grabie, S. Jang, A.H. Lichtman, A. Shimizu, N. Hogg, Loss of myeloid related protein-8/14 exacerbates cardiac allograft rejection, Circulation 124 (25) (2011) 2920–2932. C. Kerkhoff, W. Nacken, M. Benedyk, M.C. Dagher, C. Sopalla, J. Doussiere, The arachidonic acid-binding protein S100A8/A9 promotes NADPH oxidase activation by interaction with p67 phox and Rac-2, FASEB J. 19 (3) (2005) 467–469. T.E. Kehl-Fie, S. Chitayat, M.I. Hood, S. Damo, N. Restrepo, C. Garcia, K.A. Munro, W.J. Chazin, E.P. Skaar, Nutrient metal sequestration by calprotectin inhibits bacterial superoxide defense, enhancing neutrophil killing of Staphylococcus aureus, Cell Host Microbe 10 (2) (2011) 158–164. B.D. Corbin, E.H. Seeley, A. Raab, J. Feldmann, M.R. Miller, V.J. Torres, K.L. Anderson, B.M. Dattilo, P.M. Dunman, R. Gerads, Metal chelation and inhibition of bacterial growth in tissue abscesses, Science 319 (5865) (2008) 962–965. D. Viemann, K. Barczyk, T. Vogl, U. Fischer, C. Sunderkötter, K. Schulze-Osthoff, J. Roth, MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and-independent cell death program, Blood 109 (6) (2007) 2453–2460. S. Yui, Y. Nakatani, M. Mikami, Calprotectin (S100A8/S100A9), an inflammatory

Clinica Chimica Acta xxx (xxxx) xxx–xxx

X. Xiao, et al.

[77] [78] [79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102] B.J. Gentil, C. Delphin, G.O. Mbele, J.C. Deloulme, M. Ferro, J. Garin, J. Baudier, The giant protein AHNAK is a specific target for the calcium-and zinc-binding S100B protein potential implications for Ca2+ homeostasis regulation by S100B, J. Biol. Chem. 276 (26) (2001) 23253–23261. [103] J.N. Tsoporis, C.B. Overgaard, S. Izhar, T.G. Parker, S100B modulates the hemodynamic response to norepinephrine stimulation, Am. J. Hypertens. 22 (10) (2009) 1048–1053. [104] R. Donato, G. Sorci, F. Riuzzi, C. Arcuri, R. Bianchi, F. Brozzi, C. Tubaro, I. Giambanco, S100B's double life: intracellular regulator and extracellular signal, Biochim. et Biophys. Acta (BBA)-Mole. Cell Res. 1793 (6) (2009) 1008–1022. [105] R. Donato, Mechanism of action of S-100 protein (s) on brain microtubule protein assembly, Biochem. Biophys. Res. Commun. 124 (3) (1984) 850–856. [106] M. Garbuglia, M. Verzini, R. Donato, Annexin VI binds S100A1 and S100B and blocks the ability of S100A1 and S100B to inhibit desmin and GFAP assemblies into intermediate filaments, Cell Calc. 24 (3) (1998) 177–191. [107] M. Garbuglia, M. Verzini, R.R. Rustandi, D. Osterloh, D.J. Weber, V. Gerke, R. Donato, Role of the C-terminal extension in the interaction of S100A1 with GFAP, tubulin, the S100A1-and S100B-inhibitory peptide, TRTK-12, and a peptide derived from p53, and the S100A1 inhibitory effect on GFAP polymerization, Biochem. Biophys. Res. Commun. 254 (1) (1999) 36–41. [108] M. Garbuglia, M. Verzini, A. Hofmann, R. Huber, R. Donato, S100A1 and S100B interactions with annexins, Biochim. et Biophys. Acta (BBA)-Mole. Cell Res. 1498 (2–3) (2000) 192–206. [109] R. Donato, Calcium-independent, pH-regulated effects of S-100 proteins on assembly-disassembly of brain microtubule protein in vitro, J. Biol. Chem. 263 (1) (1988) 106–110. [110] R. Bianchi, I. Giambanco, R. Donato, S-100 protein, but not calmodulin, binds to the glial fibrillary acidic protein and inhibits its polymerization in a Ca (2+)dependent manner, J. Biol. Chem. 268 (17) (1993) 12669–12674. [111] M. Garbuglia, M. Verzini, I. Giambanco, A. Spreca, R. Donato, Effects of calciumbinding proteins (S-100a (o), S-100a, S-100b) on desmin assembly in vitro, FASEB J. 10 (2) (1996) 317–324. [112] G. Sorci, A. Agneletti, R. Donato, Effects of S100A1 and S100B on microtubule stability. An in vitro study using triton-cytoskeletons from astrocyte and myoblast cell lines, Neuroscience 99 (4) (2000) 773–783. [113] B. Gilquin, B.R. Cannon, A. Hubstenberger, B. Moulouel, E. Falk, N. Merle, N. Assard, S. Kieffer, D. Rousseau, P.T. Wilder, The calcium-dependent interaction between S100B and the mitochondrial AAA ATPase ATAD3A and the role of this complex in the cytoplasmic processing of ATAD3A, Mol. Cell. Biol. 30 (11) (2010) 2724–2736. [114] J. Liu, H. Wang, L. Zhang, Y. Xu, W. Deng, H. Zhu, C. Qin, S100B transgenic mice develop features of Parkinson's disease, Arch. Med. Res. 42 (1) (2011) 1–7. [115] Y. Liu, D.C. Buck, K.A. Neve, Novel interaction of the dopamine D2 receptor and the Ca2+ binding protein S100B: role in D2 receptor function, Mol. Pharmacol. 74 (2) (2008) 371–378. [116] G. Sorci, R. Bianchi, F. Riuzzi, C. Tubaro, C. Arcuri, I. Giambanco, R. Donato, S100B protein, a damage-associated molecular pattern protein in the brain and heart, and beyond, Cardiovasc. Psych. Neurol. 2010 (2010). [117] L. Zhang, W. Liu, D. Alizadeh, D. Zhao, O. Farrukh, J. Lin, S.A. Badie, B. Badie, S100B attenuates microglia activation in gliomas: possible role of STAT3 pathway, Glia 59 (3) (2011) 486–498. [118] R. Bianchi, E. Kastrisianaki, I. Giambanco, R. Donato, S100B protein stimulates microglia migration via RAGE-dependent up-regulation of chemokine expression and release, J. Biol. Chem. 286 (9) (2011) 7214–7226. [119] T. Mori, N. Koyama, G.W. Arendash, Y. Horikoshi-Sakuraba, J. Tan, T. Town, Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease, Glia 58 (3) (2010) 300–314. [120] T. Mori, J. Tan, G.W. Arendash, N. Koyama, Y. Nojima, T. Town, Overexpression of human S100B exacerbates brain damage and periinfarct gliosis after permanent focal ischemia, Stroke 39 (7) (2008) 2114–2121. [121] M.E. Choudhury, T. Moritoyo, M. Kubo, W.T. Kyaw, H. Yabe, N. Nishikawa, M. Nagai, S. Matsuda, M. Nomoto, Zonisamide-induced long-lasting recovery of dopaminergic neurons from MPTP-toxicity, Brain Res. 1384 (2011) 170–178. [122] S.S. Shaw, A.M. Schmidt, A.K. Banes, X. Wang, D.M. Stern, M.B. Marrero, S100BRAGE-mediated augmentation of angiotensin II-induced activation of JAK2 in vascular smooth muscle cells is dependent on PLD2, Diabetes 52 (9) (2003) 2381–2388. [123] K.C. Luu, G.Y. Nie, L.A. Salamonsen, Endometrial calbindins are critical for embryo implantation: evidence from in vivo use of morpholino antisense oligonucleotides, Proc. Natl. Acad. Sci. 101 (21) (2004) 8028–8033. [124] A. Malmendal, C.W. Vander Kooi, N.C. Nielsen, W.J. Chazin, Calcium-modulated S100 protein− phospholipid interactions. An NMR study of calbindin D9k and DPC, Biochemistry 44 (17) (2005) 6502–6512. [125] J. Austermann, A.R. Nazmi, C. Müller-Tidow, V. Gerke, Characterization of the Ca2+-regulated ezrin-S100P interaction and its role in tumor cell migration, J. Biol. Chem. 283 (43) (2008) 29331–29340. [126] M. Du, G. Wang, T.M. Ismail, S. Gross, D.G. Fernig, R. Barraclough, P.S. Rudland, S100P dissociates myosin IIA filaments and focal adhesion sites to reduce cell adhesion and enhance cell migration, J. Biol. Chem. 287 (19) (2012) 15330–15344. [127] T. Arumugam, C.D. Logsdon, S100P: a novel therapeutic target for cancer, Amino Acids 41 (4) (2011) 893–899. [128] A.V. Gribenko, J.E. Hopper, G.I. Makhatadze, Molecular characterization and tissue distribution of a novel member of the S100 family of EF-hand proteins, Biochemistry 40 (51) (2001) 15538–15548. [129] A. Oesterle, M.A. Hofmann Bowman, S100A12 and the S100/calgranulins:

protein complex from neutrophils with a broad apoptosis-inducing activity, Biol. Pharm. Bull. 26 (6) (2003) 753–760. P. Svenningsson, P. Greengard, p11 (S100A10)—an inducible adaptor protein that modulates neuronal functions, Curr. Opin. Pharmacol. 7 (1) (2007) 27–32. U. Rescher, V. Gerke, S100A10/p11: family, friends and functions, Pflügers Archiv-Euro. J. Physiol. 455 (4) (2008) 575–582. P.A. O'Connell, P.A. Madureira, J.N. Berman, R.S. Liwski, D.M. Waisman, Regulation of S100A10 by the PML-RAR-α oncoprotein, Blood 117 (15) (2011) 4095–4105. M. Sakaguchi, M. Miyazaki, H. Sonegawa, M. Kashiwagi, M. Ohba, T. Kuroki, M. Namba, N.-H. Huh, PKCα mediates TGFβ-induced growth inhibition of human keratinocytes via phosphorylation of S100C/A11, J. Cell Biol. 164 (7) (2004) 979–984. U. Murzik, P. Hemmerich, S. Weidtkamp-Peters, T. Ulbricht, W. Bussen, J. Hentschel, F. von Eggeling, C. Melle, Rad54B targeting to DNA double-strand break repair sites requires complex formation with S100A11, Mol. Biol. Cell 19 (7) (2008) 2926–2935. M. Sakaguchi, H. Sonegawa, H. Murata, M. Kitazoe, J.-I. Futami, K. Kataoka, H. Yamada, N.-H. Huh, S100A11, an dual mediator for growth regulation of human keratinocytes, Mol. Biol. Cell 19 (1) (2008) 78–85. M. Hanaue, N. Miwa, T. Uebi, Y. Fukuda, Y. Katagiri, K. Takamatsu, Characterization of S100A11, a suppressive factor of fertilization, in the mouse female reproductive tract, Mol. Reprod. Dev. 78 (2) (2011) 91–103. D.L. Cecil, R. Terkeltaub, Transamidation by transglutaminase 2 transforms S100A11 calgranulin into a procatabolic cytokine for chondrocytes, J. Immunol. 180 (12) (2008) 8378–8385. T. Vogl, C. Pröpper, M. Hartmann, A. Strey, K. Strupat, C. van den Bos, C. Sorg, J. Roth, S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14, J. Biol. Chem. 274 (36) (1999) 25291–25296. M. Hofmann Bowman, J. Wilk, A. Heydemann, G. Kim, J. Rehman, J.A. Lodato, J. Raman, E.M. McNally, S100A12 mediates aortic wall remodeling and aortic aneurysm, Circ. Res. 106 (1) (2010) 145–154. M.A. Hofmann Bowman, J. Gawdzik, U. Bukhari, A.N. Husain, P.T. Toth, G. Kim, J. Earley, E.M. McNally, S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E–null mice by activating an osteogenic gene regulatory program, Arterioscler. Thromb. Vasc. Biol. 31 (2) (2011) 337–344. M. Hofmann Bowman, A. Heydemann, J. Gawdzik, R.A. Shilling, B. CamorettiMercado, Transgenic expression of human S100A12 induces structural airway abnormalities and limited lung inflammation in a mouse model of allergic inflammation, Clin. Exp. Allergy 41 (6) (2011) 878–889. Z. Yang, W.X. Yan, H. Cai, N. Tedla, C. Armishaw, N. Di Girolamo, H.W. Wang, T. Hampartzoumian, J.L. Simpson, P.G. Gibson, S100A12 provokes mast cell activation: a potential amplification pathway in asthma and innate immunity, J. Allergy Clin. Immunol. 119 (1) (2007) 106–114. Y. Su, C. Xu, Z. Sun, Y. Liang, G. Li, T. Tong, J. Chen, S100A13 promotes senescence-associated secretory phenotype and cellular senescence via modulation of non-classical secretion of IL-1α, Aging (Albany NY) 11(2) (2019) 549. H.-L. Hsieh, B.W. Schäfer, B. Weigle, C.W. Heizmann, S100 protein translocation in response to extracellular S100 is mediated by receptor for advanced glycation endproducts in human endothelial cells, Biochem. Biophys. Res. Commun. 316 (3) (2004) 949–959. K.M. Kathir, K. Ibrahim, D. Rajalingam, I. Prudovsky, C. Yu, T.K.S. Kumar, S100A13–lipid interactions—role in the non-classical release of the acidic fibroblast growth factor, Biochim. et Biophys. Acta (BBA)-Biomembr. 1768 (12) (2007) 3080–3089. S. Hayrabedyan, S. Kyurkchiev, I. Kehayov, FGF-1 and S100A13 possibly contribute to angiogenesis in endometriosis, J. Reprod. Immunol. 67 (1–2) (2005) 87–101. D. Sapkota, O. Bruland, D.E. Costea, H. Haugen, E.N. Vasstrand, S.O. Ibrahim, S100A14 regulates the invasive potential of oral squamous cell carcinoma derived cell-lines in vitro by modulating expression of matrix metalloproteinases, MMP1 and MMP9, Eur. J. Cancer 47 (4) (2011) 600–610. H. Chen, Y. Yuan, C. Zhang, A. Luo, F. Ding, J. Ma, S. Yang, Y. Tian, T. Tong, Q. Zhan, Involvement of S100A14 protein in cell invasion by affecting expression and function of matrix metalloproteinase (MMP)-2 via p53-dependent transcriptional regulation, J. Biol. Chem. 287 (21) (2012) 17109–17119. H. Chen, A. Luo, F. Ding, Z. Liu, S100A14 stimulates cell proliferation and induces cell apoptosis at different concentrations via receptor for advanced glycation end products (RAGE), PLoS ONE 6 (4) (2011) e19375. R. Gläser, U. Meyer-Hoffert, J. Harder, J. Cordes, M. Wittersheim, J. Kobliakova, R. Fölster-Holst, E. Proksch, J.-M. Schröder, T. Schwarz, The antimicrobial protein psoriasin (S100A7) is upregulated in atopic dermatitis and after experimental skin barrier disruption, J. Invest. Dermatol. 129 (3) (2009) 641–649. A.S. Büchau, M. Hassan, G. Kukova, V. Lewerenz, S. Kellermann, J.U. Würthner, R. Wolf, M. Walz, R.L. Gallo, T. Ruzicka, S100A15, an antimicrobial protein of the skin: regulation by E. coli through Toll-like receptor 4, J. Invest. Dermatol. 127 (11) (2007) 2596–2604. E. Sturchler, J.A. Cox, I. Durussel, M. Weibel, C.W. Heizmann, S100A16, a novel calcium-binding protein of the EF-hand superfamily, J. Biol. Chem. 281 (50) (2006) 38905–38917. Y. Liu, R. Zhang, J. Xin, Y. Sun, J. Li, D. Wei, A.Z. Zhao, Identification of S100A16 as a novel adipogenesis promoting factor in 3T3-L1 cells, Endocrinology 152 (3) (2011) 903–911. Z.-G. Xiong, D. O'Hanlon, L.E. Becker, J. Roder, J.F. MacDonald, A. Marks, Enhanced calcium transients in glial cells in neonatal cerebellar cultures derived from S100B null mice, Exp. Cell Res. 257 (2) (2000) 281–289.

10

Clinica Chimica Acta xxx (xxxx) xxx–xxx

X. Xiao, et al.

[130] [131]

[132]

[133]

[134]

[135]

[136]

[137]

[138]

[139]

[140]

[141]

[142]

[143]

[144]

[145]

[146]

[147]

[148]

[149]

[150]

[151]

[152]

[153]

[154] [155]

mellitus, Circulation 115 (12) (2007) 1544–1550. [156] Y. Kayama, U. Raaz, A. Jagger, M. Adam, I. Schellinger, M. Sakamoto, H. Suzuki, K. Toyama, J. Spin, P. Tsao, Diabetic cardiovascular disease induced by oxidative stress, Int. J. Mol. Sci. 16 (10) (2015) 25234–25263. [157] D. Yao, M. Brownlee, Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands, Diabetes 59 (1) (2010) 249–255. [158] F.J. Ortega, M. Sabater, J.M. Moreno-Navarrete, N. Pueyo, P. Botas, E. Delgado, W. Ricart, G. Frühbeck, J.M. Fernández-Real, Serum and urinary concentrations of calprotectin as markers of insulin resistance and type 2 diabetes, Eur. J. Endocrinol. 167 (4) (2012) 569–578. [159] O.S. Cotoi, P. Dunér, N. Ko, B. Hedblad, J. Nilsson, H. Björkbacka, A. Schiopu, Plasma S100A8/A9 correlates with blood neutrophil counts, traditional risk factors, and cardiovascular disease in middle-aged healthy individuals, Arterioscler. Thromb. Vasc. Biol. 34 (1) (2014) 202–210. [160] P. Zhao, M. Wu, H. Yu, Y. Huang, Y. Wang, W. Wang, W. Yin, Serum S100A12 levels are correlated with the presence and severity of coronary artery disease in patients with type 2 diabetes mellitus, J. Invest. Med. 61 (5) (2013) 861–866. [161] F. Touré, G. Fritz, Q. Li, V. Rai, G. Daffu, Y.S. Zou, R. Rosario, R. Ramasamy, A.S. Alberts, S.F. Yan, Formin mDia1 mediates vascular remodeling via integration of oxidative and signal transduction pathways, Circ. Res. 110 (10) (2012) 1279–1293. [162] K. Boström, K. Watson, S. Horn, C. Wortham, I. Herman, L. Demer, Bone morphogenetic protein expression in human atherosclerotic lesions, J. Clin. Investig. 91 (4) (1993) 1800–1809. [163] L. Fitzpatrick, A. Severson, W. Edwards, R. Ingram, Diffuse calcification in human coronary arteries. Association of osteopontin with atherosclerosis, J. Clin. Invest. 94 (4) (1994) 1597–1604. [164] J. Andrews, P.J. Psaltis, B.A. Di Bartolo, S.J. Nicholls, R. Puri, Coronary arterial calcification: a review of mechanisms, promoters and imaging, Trends Cardiovasc. Med. 28 (8) (2018) 491–501. [165] A.B. Reiss, N. Miyawaki, J. Moon, L.J. Kasselman, I. Voloshyna, R. D'Avino Jr, J. De Leon, CKD, arterial calcification, atherosclerosis and bone health: Inter-relationships and controversies, Atherosclerosis (2018). [166] V. Iyemere, D. Proudfoot, P. Weissberg, C. Shanahan, Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification, J. Intern. Med. 260 (3) (2006) 192–210. [167] A. Cmoch, A. Strzelecka-Kiliszek, M. Palczewska, P. Groves, S. Pikula, Matrix vesicles isolated from mineralization-competent Saos-2 cells are selectively enriched with annexins and S100 proteins, Biochem. Biophys. Res. Commun. 412 (4) (2011) 683–687. [168] M.A.H. Bowman, E.M. McNally, Genetic pathways of vascular calcification, Trends Cardiovasc. Med. 22 (4) (2012) 93–98. [169] A.N. Kapustin, M.L. Chatrou, I. Drozdov, Y. Zheng, S.M. Davidson, D. Soong, M. Furmanik, P. Sanchis, R.T.M. De Rosales, D. Alvarez-Hernandez, Vascular smooth muscle cell calcification is mediated by regulated exosome secretion, Circ. Res. 116 (8) (2015) 1312–1323. [170] S.E. New, E. Aikawa, Role of extracellular vesicles in de novo mineralization: an additional novel mechanism of cardiovascular calcification, Arterioscler. Thromb. Vasc. Biol. 33 (8) (2013) 1753–1758. [171] J. Gawdzik, L. Mathew, G. Kim, T.S. Puri, M.A.H. Bowman, Vascular remodeling and arterial calcification are directly mediated by S100A12 (EN-RAGE) in chronic kidney disease, Am. J. Nephrol. 33 (3) (2011) 250–259. [172] N. Isoyama, P. Leurs, A.R. Qureshi, A. Bruchfeld, B. Anderstam, O. Heimburger, P. Bárány, P. Stenvinkel, B. Lindholm, Plasma S100A12 and soluble receptor of advanced glycation end product levels and mortality in chronic kidney disease stage 5 patients, Nephrol. Dial. Transplant. 30 (1) (2014) 84–91. [173] J. Goyette, W.X. Yan, E. Yamen, Y.M. Chung, S.Y. Lim, K. Hsu, F. Rahimi, N. Di Girolamo, C. Song, W. Jessup, Pleiotropic roles of S100A12 in coronary atherosclerotic plaque formation and rupture, J. Immunol. 183 (1) (2009) 593–603. [174] D.M. Karussis, D. Lehmann, S. Slavin, U. Vourka-Karussis, R. Mizrachi-Koll, H. Ovadia, T. Kalland, O. Abramsky, Treatment of chronic-relapsing experimental autoimmune encephalomyelitis with the synthetic immunomodulator linomide (quinoline-3-carboxamide), Proceedings of the National Academy of Sciences, 1993, pp. 6400–6404. [175] A. Tarkowski, K. Gunnarsson, T. Stålhandske, Effects of LS-2616 administration upon the autoimmune disease of (NZB x NZW) F1 hybrid mice, Immunology 59 (4) (1986) 589. [176] J. Björk, S. Kleinau, Paradoxical effects of LS-2616 (Linomide) treatment in the type II collagen arthritis model in mice, Agents Actions 27 (3–4) (1989) 319–321. [177] C. Brunmark, A. Runström, L. Ohlsson, B. Sparre, T. Brodin, M. Åström, G. Hedlund, The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis, J. Neuroimmunol. 130 (1–2) (2002) 163–172. [178] P. Björk, A. Björk, T. Vogl, M. Stenström, D. Liberg, A. Olsson, J. Roth, F. Ivars, T. Leanderson, Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides, PLoS Biol. 7 (4) (2009) e1000097. [179] A. Stocca, D. O’Toole, N. Hynes, S. Hynes, K. Mashayekhi, L. McGinley, E. O’Connell, C. Coleman, S. Sultan, A. Duffy, A role for MRP8 in in stent restenosis in diabetes, Atherosclerosis 221 (2) (2012) 325–332. [180] N. Kipshidze, G. Dangas, M. Tsapenko, J. Moses, M.B. Leon, M. Kutryk, P. Serruys, Role of the endothelium in modulating neointimal formation: vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions, J. Am. Coll. Cardiol. 44 (4) (2004) 733–739. [181] L. Wang, H. Luo, X. Chen, Y. Jiang, Q. Huang, Functional characterization of

emerging biomarkers for atherosclerosis and possibly therapeutic targets, Arterioscler. Thromb. Vasc. Biol. 35 (12) (2015) 2496–2507. M.M. Averill, C. Kerkhoff, K.E. Bornfeldt, S100A8 and S100A9 in cardiovascular biology and disease, Arterioscler. Thromb. Vasc. Biol. 32 (2) (2012) 223–229. N.K. Schiller, W.A. Boisvert, L.K. Curtiss, Inflammation in atherosclerosis: lesion formation in LDL receptor-deficient mice with perforin and Lyst beige mutations, Arterioscler. Thromb. Vasc. Biol. 22 (8) (2002) 1341–1346. C.F. Urban, D. Ermert, M. Schmid, U. Abu-Abed, C. Goosmann, W. Nacken, V. Brinkmann, P.R. Jungblut, A. Zychlinsky, Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans, PLoS Pathog. 5 (10) (2009) e1000639. K. De Filippo, D.R. Neill, M. Mathies, M. Bangert, E. McNeill, A. Kadioglu, N. Hogg, A new protective role for S100A9 in regulation of neutrophil recruitment during invasive pneumococcal pneumonia, FASEB J. 28 (8) (2014) 3600–3608. M.A. Hofmann, S. Drury, C. Fu, W. Qu, A. Taguchi, Y. Lu, C. Avila, N. Kambham, A. Bierhaus, P. Nawroth, RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides, Cell 97 (7) (1999) 889–901. L. Yan, L. Mathew, B. Chellan, B. Gardner, J. Earley, T.S. Puri, M.A. Hofmann Bowman, S100/Calgranulin-mediated inflammation accelerates left ventricular hypertrophy and aortic valve sclerosis in chronic kidney disease in a receptor for advanced glycation end products–dependent manner, Arterioscler. Thromb. Vasc. Biol. 34 (7) (2014) 1399–1411. T. Vogl, K. Tenbrock, S. Ludwig, N. Leukert, C. Ehrhardt, M.A. Van Zoelen, W. Nacken, D. Foell, T. Van der Poll, C. Sorg, Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock, Nat. Med. 13 (9) (2007) 1042. M. Neeper, A. Schmidt, J. Brett, S. Yan, F. Wang, Y. Pan, K. Elliston, D. Stern, A. Shaw, Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins, J. Biol. Chem. 267 (21) (1992) 14998–15004. L. Yan, P. Bjork, R. Butuc, J. Gawdzik, J. Earley, G. Kim, M.A.H. Bowman, Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE null mice, Atherosclerosis 228 (1) (2013) 69–79. G. Srikrishna, J. Nayak, B. Weigle, A. Temme, D. Foell, L. Hazelwood, A. Olsson, N. Volkmann, D. Hanein, H.H. Freeze, Carboxylated N-glycans on RAGE promote S100A12 binding and signaling, J. Cell. Biochem. 110 (3) (2010) 645–659. M.A.H. Bowman, A.M. Schmidt, The next generation of RAGE modulators: implications for soluble RAGE therapies in vascular inflammation, J. Mol. Med. 91 (12) (2013) 1329–1331. L. Ma, P. Sun, J.-C. Zhang, Q. Zhang, S.-L. Yao, Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells, Int. J. Mol. Med. 40 (1) (2017) 31–38. K. Croce, H. Gao, Y. Wang, T. Mooroka, M. Sakuma, C. Shi, G. Sukhova, R.R. Packard, N. Hogg, P. Libby, MRP-8/14 is critical for the biological response to vascular injury, Circulation 120 (5) (2009) 427. W.X. Yan, C. Armishaw, J. Goyette, Z. Yang, H. Cai, P. Alewood, C.L. Geczy, Mast cell and monocyte recruitment by S100A12 and its hinge domain, J. Biol. Chem. 283 (19) (2008) 13035–13043. S. Hoppmann, J. Steinbach, J. Pietzsch, Scavenger receptors are associated with cellular interactions of S100A12 in vitro and in vivo, Int. J. Biochem. Cell Biol. 42 (5) (2010) 651–661. C. Tondera, M. Laube, J. Pietzsch, Insights into binding of S100 proteins to scavenger receptors: class B scavenger receptor CD36 binds S100A12 with high affinity, Amino Acids 49 (1) (2017) 183–191. M. Lackmann, P. Rajasekariah, S. Iismaa, G. Jones, C. Cornish, S. Hu, R. Simpson, R. Moritz, C. Geczy, Identification of a chemotactic domain of the pro-inflammatory S100 protein CP-10, J. Immunol. 150 (7) (1993) 2981–2991. J.M. Devery, N. King, C. Geczy, Acute inflammatory activity of the S100 protein CP-10. Activation of neutrophils in vivo and in vitro, J. Immunol. 152 (4) (1994) 1888–1897. C. Kerkhoff, C. Sorg, N.N. Tandon, W. Nacken, Interaction of S100A8/S100A9− arachidonic acid complexes with the scavenger receptor CD36 may facilitate fatty acid uptake by endothelial cells, Biochemistry 40 (1) (2001) 241–248. M. Sakuma, A. Tanaka, N. Kotooka, Y. Hikichi, S. Toyoda, S. Abe, I. Taguchi, K. Node, D.I. Simon, T. Inoue, Myeloid-related protein-8/14 in acute coronary syndrome, Int. J. Cardiol. 249 (2017) 25–31. B.I. Hudson, A.Z. Kalea, M. del Mar Arriero, E. Harja, E. Boulanger, V. D'Agati, A.M. Schmidt, Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42, J. Biol. Chem. 283 (49) (2008) 34457–34468. C.H. Byon, A. Javed, Q. Dai, J.C. Kappes, T.L. Clemens, V.M. Darley-Usmar, J.M. McDonald, Y. Chen, Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling, J. Biol. Chem. 283 (22) (2008) 15319–15327. P.R. Nagareddy, A.J. Murphy, R.A. Stirzaker, Y. Hu, S. Yu, R.G. Miller, B. Ramkhelawon, E. Distel, M. Westerterp, L.-S. Huang, Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis, Cell Metab. 17 (5) (2013) 695–708. S.Y. Lim, M.J. Raftery, J. Goyette, K. Hsu, C.L. Geczy, Oxidative modifications of S100 proteins: functional regulation by redox, J. Leukoc. Biol. 86 (3) (2009) 577–587. A. Faria, S.J. Persaud, Cardiac oxidative stress in diabetes: mechanisms and therapeutic potential, Pharmacol. Ther. 172 (2017) 50–62. C.S. Fox, S. Coady, P.D. Sorlie, R. D’Agostino, M.J. Pencina, R.S. Vasan, J. Meigs, D. Levy, P. Savage, Increasing cardiovascular disease burden due to diabetes

11

Clinica Chimica Acta xxx (xxxx) xxx–xxx

X. Xiao, et al.

[182]

[183]

[184] [185]

[186]

[187] [188]

[189]

[190]

S100A8 and S100A9 in altering monolayer permeability of human umbilical endothelial cells, PLoS ONE 9 (3) (2014) e90472. D.Y. Lu, E.Y. Chen, D.J. Wong, K. Yamamoto, C.D. Protack, W.T. Williams, R. Assi, M.R. Hall, N. Sadaghianloo, A. Dardik, Vein graft adaptation and fistula maturation in the arterial environment, J. Surg. Res. 188 (1) (2014) 162–173. L. Bao, A.F. Odell, S.L. Stephen, S.B. Wheatcroft, J.H. Walker, S. Ponnambalam, The S 100A6 calcium-binding protein regulates endothelial cell-cycle progression and senescence, FEBS J. 279 (24) (2012) 4576–4588. C. Chaabane, F. Otsuka, R. Virmani, M.-L. Bochaton-Piallat, Biological responses in stented arteries, Cardiovasc. Res. 99 (2) (2013) 353–363. M. Bartoli, X. Gu, N.T. Tsai, R.C. Venema, S.E. Brooks, M.B. Marrero, R.B. Caldwell, Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells, J. Biol. Chem. 275 (43) (2000) 33189–33192. T. Decker, P. Kovarik, Transcription factor activity of STAT proteins: structural requirements and regulation by phosphorylation and interacting proteins, Cell. Mole. Life Sci. CMLS 55 (12) (1999) 1535–1546. G. Yang, Y. Xu, X. Chen, G. Hu, IFITM1 plays an essential role in the antiproliferative action of interferon-γ, Oncogene 26 (4) (2007) 594. C. Lerchenmüller, J. Heißenberg, F. Damilano, V.J. Bezzeridis, I. Krämer, M.L. Bochaton-Piallat, K. Hirschberg, M. Busch, H.A. Katus, K. Peppel, S100A6 regulates endothelial cell cycle progression by attenuating antiproliferative signal transducers and activators of transcription 1 signaling, Arterioscler. Thromb. Vasc. Biol. 36 (9) (2016) 1854–1867. A. Kosaki, T. Hasegawa, T. Kimura, K. Iida, J. Hitomi, H. Matsubara, Y. Mori, M. Okigaki, N. Toyoda, H. Masaki, Increased plasma S100A12 (EN-RAGE) levels in patients with type 2 diabetes, J. Clin. Endocrinol. Metab. 89 (11) (2004) 5423–5428. G. Basta, A.M. Sironi, G. Lazzerini, S. Del Turco, E. Buzzigoli, A. Casolaro,

[191]

[192]

[193]

[194]

[195]

[196]

12

A. Natali, E. Ferrannini, A. Gastaldelli, Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein, J. Clin. Endocrinol. Metab. 91 (11) (2006) 4628–4634. O.H. Mortensen, A.R. Nielsen, C. Erikstrup, P. Plomgaard, C.P. Fischer, R. KroghMadsen, B. Lindegaard, A.M. Petersen, S. Taudorf, B.K. Pedersen, Calprotectin—a novel marker of obesity, PLoS ONE 4 (10) (2009) e7419. V. Catalán, J. Gómez-Ambrosi, A. Rodríguez, B. Ramírez, F. Rotellar, V. Valentí, C. Silva, M.J. Gil, J.M. Fernández-Real, J. Salvador, Increased levels of calprotectin in obesity are related to macrophage content: impact on inflammation and effect of weight loss, Mol. Med. 17 (11–12) (2011) 1157–1167. D.A. Morrow, Y. Wang, K. Croce, M. Sakuma, M.S. Sabatine, H. Gao, A.D. Pradhan, A.M. Healy, J. Buros, C.H. McCabe, Myeloid-related protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute coronary syndrome in the Pravastatin or atorvastatin evaluation and infection theraphy: thrombolysis in myocardial infarction (PROVE IT-TIMI 22) trial, Am. Heart J. 155 (1) (2008) 49–55. A. Nakashima, J.J. Carrero, A.R. Qureshi, T. Miyamoto, B. Anderstam, P. Bárány, O. Heimbürger, P. Stenvinkel, B. Lindholm, Effect of circulating soluble receptor for advanced glycation end products (sRAGE) and the proinflammatory RAGE ligand (EN-RAGE, S100A12) on mortality in hemodialysis patients, Clin. J. Am. Soc. Nephrol. 5 (12) (2010) 2213–2219. Y. Shiotsu, Y. Mori, M. Nishimura, C. Sakoda, T. Tokoro, T. Hatta, N. Maki, K. Iida, N. Iwamoto, T. Ono, Plasma S100A12 level is associated with cardiovascular disease in hemodialysis patients, Clin. J. Am. Soc. Nephrol. 6 (4) (2011) 718–723. S. Ligthart, S. Sedaghat, M.A. Ikram, A. Hofman, O.H. Franco, A. Dehghan, ENRAGE: a novel inflammatory marker for incident coronary heart disease, Arterioscler. Thromb. Vasc. Biol. 34 (12) (2014) 2695–2699.