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Bradykinin Peptides
Chapter 188
Bradykinin Peptides Duncan John Campbell
ABSTRACT The kallikrein–kinin system (KKS) generates a family of bioactive peptides with varying biological activities. These include hydroxylated and nonhydroxylated bradykinin and kallidin (Lys0-bradykinin) peptides and their respective carboxypeptidase metabolites, des-Arg9-bradykinin and des-Arg10-kallidin. Although bradykinin and kallidin act mainly via the bradykinin type 2 (B2) receptor, des-Arg9-bradykinin and des-Arg10-kallidin act mainly via the bradykinin type 1 (B1) receptor. Kinins are potent vasodilators, promote natriuresis and diuresis, and have beneficial cardiovascular effects; however, kinins may also promote inflammation. Peptidases are important determinants of kinin levels, and increased kinin levels may contribute to both the beneficial and adverse effects of peptidase inhibitor therapy.
DISCOVERY Bradykinin and its related peptides are generated by the action of kallikrein enzymes on kininogen substrates. Initial discoveries of the kallikrein–kinin system (KKS) took place in the laboratories of Frey and Kraut in Germany (reviewed by Werle35) and Roche e Silva in Brazil.30 In the laboratory of Frey and Kraut, kallikrein-like activity was initially revealed by the hypotensive effects of intravenous injection of urine.35 It was also found that plasma and serum deactivate this activity. Subsequent isolation of this hypotensive material in large amounts from the pancreas led to it being named kallikrein, although it was evident that the pancreas was not the only source of kallikrein. Kallikrein could be extracted from the pancreas in both the active and inactive forms. A similar hypotensive material was also isolated from plasma in both the active and inactive forms and was named plasma kallikrein. Moreover, the inactive forms of kallikrein were activated by trypsin. The biological activity of kallikrein extracted from the submandibular salivary gland was found to be due to its enzymatic release of a low-molecular-weight, thermostable compound from a serum protein. This low-molecular-weight compound, 1386
believed to be a polypeptide, was initially called DK, and later called kallidin, and its inactive precursor was called kallidinogen.35 In the laboratory of Roche e Silva, bradykinin was initially identified as a hypotensive and smooth musclestimulating factor released from plasma globulin by snake venoms and by trypsin.30 It was named bradykinin because it produced a slow contraction of the guinea pig ileum.30 Trypsin digestion of an ammonium sulfate fraction from ox serum produced the nonapeptide bradykinin, the sequence of which was reported by Elliott et al. in 1960.13 However, digestion of human plasma with human urinary kallikrein produced two peaks of bioactivity, one (named kallidin I) corresponding to bradykinin and a second (named kallidin II) that corresponded to lysine bradykinin.27 Because human urinary kallikrein can hydrolyze synthetic arginine esters but not lysine esters, Pierce and Webster concluded that human urinary kallikrein produced lysine bradykinin (now known as kallidin).27
STRUCTURE OF KININOGEN mRNA AND GENE Kininogens are glycoproteins that contain the bradykinin sequence in their midportion. There are two forms of kininogen that differ in structure, size, and susceptibility to cleavage by plasma and tissue kallikreins.3 Human highmolecular-weight kininogen (HMWK) has 626 amino acids, with a mass of 88–120 kDa, whereas human low-molecularweight kininogen (LMWK) has 409 amino acids, with a mass of 50–68 kDa.32 The human kininogen gene encompasses 11 exons spanning approximately 27 kb and codes for both HMWK and LMWK by differential splicing of the initial messenger RNA (mRNA) transcript (Fig. 1).18,32 In the rat, T-kininogen (major acute phase protein) is a potential precursor for Ile,Ser-bradykinin and Met,Ile,Ser-bradykinin.14 However, there is no evidence that T-kininogen is a precursor of kinin peptides in vivo.9 Handbook of Biologically Active Peptides. http://dx.doi.org/10.1016/B978-0-12-385095-9.00188-3 Copyright © 2013 Elsevier Inc. All rights reserved.
SECTION | XIV Handbook of Biologically Active Peptides: Cardiovascular Peptides
Kininogen gene
Kininogen gene 10BK
Exons 1-9
1387
10HMW
11
LMWK
HMWK
Tissue kallikrein LMWK mRNA Exons 1-9
10BK
10HMW
poly A
poly A
LMWK Heavy chain BK Light chain 362 aa 9 aa 38 aa
hydroxylated
Plasma kallikrein
HMWK mRNA
Exons 1-9 10BK 11
Nonhydroxylated
Aminopeptidase Kallidin KBK-(1-9) Hyp3-KBK-(1-9)
Bradykinin BK-(1-9) Hyp3-BK-(1-9)
HMWK Heavy chain 362 aa
BK 9 aa
Light chain 255 aa
FIGURE 1 Diagrammatic representation of differential splicing of the kininogen gene transcript that produces high-molecular-weight kininogen (HMWK) and low-molecular-weight kininogen (LMWK) mRNA. HMWK represents exons 1–9 spliced to the whole of exon 10, whereas LMWK represents exons 1–9 and the first 78 base pairs of exon 10 spliced to exon 11.18,32 Both HMWK and LMWK contain the bradykinin (BK) sequence in their midportion, between their respective heavy and light chains. aa, amino acid. Not drawn to scale.
PROCESSING OF THE PRECURSOR Bradykinin and kallidin are released from kininogens predominantly by the action of the serine proteases plasma kallikrein and tissue kallikrein. Plasma kallikrein is initially secreted as the inactive prekallikrein, and tissue kallikrein is initially secreted as inactive prokallikrein. Both plasma prekallikrein and tissue prokallikrein are activated by serine protease activity. Although a single gene codes for plasma prekallikrein, there is a large family of tissue prokallikrein genes that code for tissue-kallikrein-like serine proteases. In humans, Klk1 codes for true tissue kallikrein, the only member of the tissuekallikrein-like family of serine proteases known to generate kinin peptides.20 However, in rats, true tissue kallikrein is referred to as Klk1b3, although Lundwall et al. recommended that this sequence be given the gene symbol Klk1.20 In humans, plasma kallikrein forms bradykinin from HMWK, whereas tissue kallikrein forms kallidin from HMWK and LMWK (Figs 2 and 3). By contrast, both plasma and tissue kallikrein generate bradykinin in rodents.3,5 In humans, a proportion of kininogens are hydroxylated on Pro3 of the bradykinin sequence, leading to the formation of hydroxylated kinin peptides (Hyp3-bradykinin and Hyp4kallidin). Hydroxylated kinins have biological activities that are similar to those of nonhydroxylated kinins.29 Alternative pathways of kinin formation involving enzymes other than kallikreins may operate in disease states.5 Although LMWK is a poor substrate for plasma kallikrein, cleavage by neutrophil elastase renders it much more susceptible to cleavage by plasma kallikrein to release bradykinin. Moreover, the combination of mast cell tryptase and neutrophil elastase releases bradykinin from oxidized kininogens that are resistant to cleavage by kallikreins.
Carboxypeptidase
Carboxypeptidase B2 receptor
KBK-(1-8) Hyp3-KBK-(1-8)
Aminopeptidase
BK-(1-8) Hyp3-BK-(1-8)
B1 receptor
FIGURE 2 Overview of the kallikrein–kinin system in humans. LMWK, low-molecular-weight kininogen; HMWK, high-molecular-weight kininogen; Hyp, hydroxyproline. A proportion of kininogen is hydroxylated on the third amino acid (Hyp3) of the bradykinin sequence of the precursor. Thus, bradykinin peptides may be nonhydroxylated [BK-(1-9)] or hydroxylated [Hyp3-BK-(1-9)]. Kallidin is Lys0-bradykinin and may also be either non-hydroxylated [KBK-(1-9)] or hydroxylated [Hyp3-KBK-(1-9)]. Similarly, the carboxypeptidase metabolites des-Arg9-BK-(1-9) and desArg9-KBK-(1-9) may also be either non-hydroxylated [BK-(1-8), KBK(1-8)] or hydroxylated [Hyp3-BK-(1-8), Hyp3-KBK-(1-8)]. Tissue kallikrein Plasma kallikrein HMW & LMW kininogen -Ser-Leu-Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Ser-Ser-Leu-Met-Lys-Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg-Ser0 1 2 3 4 5 6 7 8 9 B2 receptor agonists Bradykinin [BK-(1-9)] Kallidin [KBK-(1-9)] Hyp3-BK-(1-9) Hyp3-KBK-(1-9) B1 receptor agonists Bradykinin [BK-(1-8)] Kallidin [KBK-(1-8)] Hyp3-BK-(1-8) Hyp3-KBK-(1-8)
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg Lys-Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe Lys-Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe
FIGURE 3 Amino acid sequences of the agonists of the type 1 (B1) and type 2 (B2) bradykinin receptors. Hyp, hydroxyproline. Bradykinin [BK-(19)] and kallidin [Lys0-bradykinin, KBK-(1-9)] are excised from the interior of the kininogen molecules. Tissue kallikrein cleaves both HMWK and LMWK between Met379 and Lys380 (the same numbering for human HMWK and LMWK precursors) to produce the amino-terminus and between Arg389 and Ser390 to produce the carboxy-terminus of kallidin. Plasma kallikrein cleaves HMWK between Lys380 and Arg381 to produce the amino-terminus and between Arg389 and Ser390 to produce the carboxy-terminus of bradykinin.
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Endopeptidase 24.15
Angiotensin converting enzyme
TABLE 1 Blood Kinin Peptide Levels in Humans
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Aminopeptidase P Dipeptidyl peptidase IV
Endopeptidase 24.11
Prolylendopeptidase
Carboxypeptidase N Carboxypeptidase M Endothelin converting enzyme
FIGURE 4 Metabolism of bradykinin. Carboxypeptidase N is known as kininase I and angiotensin-converting enzyme is also known as kininase II. Carboxypeptidases M and N produce sequential cleavage of amino acids from the carboxy-terminus of the peptide. Aminopeptidase P produces sequential cleavage of amino acids from the amino-terminus of the peptide. Angiotensin-converting enzyme is a carboxy dipeptidase that produces sequential cleavage of dipeptides from the carboxy-terminus of the peptide. Dipeptidyl peptidase IV cleaves des-Arg1-bradykinin.
Kinin production in vivo is controlled partly by endogenous inhibitors of the kallikrein enzymes. The main inhibitors of plasma kallikrein are C1 esterase inhibitor, α2-macroglobulin, and antithrombin III.3 An important inhibitor of tissue kallikrein is kallistatin, although there is continuing uncertainty about the function of kallistatin in vivo.5 Kinin peptide metabolism is an important determinant of kinin levels in blood and tissue. Many different peptidases participate in the conversion of bradykinin and kallidin to alternative bioactive peptides and their degradation (Fig. 4). Aminopeptidase-mediated cleavage of kallidin generates bradykinin. Carboxypeptidase (kininase I)-mediated cleavage converts bradykinin and kallidin, which are more potent on the type 2 (B2) bradykinin receptor, to des-Arg9-bradykinin and des-Arg10-kallidin, respectively, which are also bioactive and more potent on the type 1 (B1) receptor (Fig. 2).29 Thus, there are 8 bioactive kinin peptides in humans, hydroxylated and nonhydroxylated bradykinin and kallidin peptides, and their carboxypeptidase metabolites (Fig. 3). Angiotensin-converting enzyme (ACE) plays an important role in bradykinin metabolism, producing bradykinin-(1-5) [BK-(1-5)], the most abundant bradykinin metabolite,23 by sequential cleavage of dipeptides from the carboxy-terminus of bradykinin. Other peptidases play a greater role in kinin peptide metabolism during ACE inhibition.
DISTRIBUTION OF KININOGEN AND KALLIKREIN mRNA, AND KININ PEPTIDES The liver is the main site of kininogen production and, in humans, HMWK mRNA is also found in the kidney, pancreas, placenta, heart, and colon, whereas LMWK mRNA is found in the kidney, brain, placenta, testis, pancreas, thymus, heart, spleen, lung, colon, and small intestine.24 Plasma prekallikrein mRNA is present in all tissues examined and is most abundantly present in the liver and
Peptide (fmol/mL)
Placebo
BK-(1-7)
1.4 (0.5–4.3)
BK-(1-8)
0.08 (0.02–0.41)
BK-(1-9)
0.18 (0.02–1.90)
Hyp3-BK-(1-7)
<0.14
Hyp3-BK-(1-8)
0.53 (0.12–2.37)
Hyp3-BK-(1-9)
0.18 (0.04–0.91)
KBK-(1-7)
0.46 (0.07–3.33)
KBK-(1-8)
0.10 (0.01–1.35)
KBK-(1-9)
0.22 (0.02–2.70)
Hyp3-KBK-(1-7)
0.04 (0.01–0.49)
Hyp3-KBK-(1-8)
<0.03
Hyp3-KBK-(1-9)
0.04 (0.01–0.26)
Data shown as geometric mean (95% confidence interval), n = 19 for bradykinin (BK) peptides; n = 18 for kallidin (KBK) peptides. Hyp, hydroxyproline. Data from Campbell et al.10
pancreas.24 In humans, the Klk1 gene is highly expressed in the kidney, pancreas, salivary gland, endometrium, ovary, skin, and pituitary.12 Other sites of Klk1 gene expression include the colon, heart, blood vessels, and adrenal.25,26,28 Bradykinin peptides are present in all tissues studied (blood, heart, aorta, brown adipose tissue, adrenal, lung, and brain).9 In humans, circulating levels of kinin peptides are low, usually <3 fmol/mL (Table 1). Studies in rats show that the levels of bradykinin in tissues are higher than in blood,9 and in humans, bradykinin and kallidin peptide levels are higher in venous than in arterial blood,5 consistent with the tissue being the main site of formation of these peptides. Bradykinin peptides are more abundant than kallidin peptides in the blood and atrial tissue of humans.5,10 In human urine, kallidin peptides are more abundant than bradykinin peptides, and the levels are several orders of magnitude higher than that in blood.5
RECEPTORS AND SIGNALING CASCADES In the basal state, the B2 receptor is constitutively expressed throughout and mediates the majority of the vascular and metabolic actions of kinins, whereas the B1 receptor is not detectable but is induced by a variety of pathological conditions, including inflammation, toxins, cytokines, and tissue trauma.19,22 Both B1 and B2 receptors can be expressed by the same cell types: vascular endothelial and smooth muscle cells, nonvascular smooth muscle such as the uterus and
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intestine, fibroblasts, epithelial cells, various tumor cells, and also on leukocytes and in the central nervous system.19 Immunohistochemical studies show a different distribution of B2 receptors in arteries and arterioles. B2 receptors are predominant in the endothelium of arteries with minor immunohistochemical staining in smooth muscle cells, whereas there is intense staining of the tunic media and minor staining of the endothelium of arterioles.5 The pharmacology of kinin receptors has been reviewed by Leeb-Lundberg et al.19 The B1 and B2 receptors are G protein-coupled, 7-transmembrane-spanning receptors. The B2 receptor signals through Gαq, and also interacts with Gαs and Gαq12/13. Stimulation of the Gαq-sensitive phospholipase Cß produces phosphoinositol hydrolysis and increased intracellular free Ca2+. Moreover, translocation of protein kinase C isoenzymes α, ε, and ζ has been observed in fibroblasts and endothelial cells. B2 receptor stimulation can also result in phospholipase A2 and phospholipase D activation.19 These second messenger systems result in stimulation of endothelial nitric oxide synthase and nitric oxide production through Ca2+-mediated mechanisms in endothelial cells, in addition to cellular release of prostacyclin, reactive oxygen species, and tissue-type plasminogen activator. The B1 receptor interacts with Gαq, and Gαi, through which it stimulates many of the same signaling pathways as the B2 receptor, including phosphoinositol hydrolysis, elevation of intracellular free Ca2+, arachidonic acid release, eicosanoid production, endothelial nitric oxide synthase activation, and nitric oxide production. Although they seem to couple to similar cellular signaling pathways, the pattern of signaling of B1 and B2 receptors may differ. In vascular smooth muscle cells, B2 receptor stimulation leads to transient phosphoinositol hydrolysis that exhibits little dependence on extracellular Ca2+, whereas B1 receptor stimulation is more sustained and significantly dependent on extracellular Ca2+. Moreover, the B2 receptor elicits a transient increase in intracellular Ca2+, whereas the B1 receptor elicits a sustained signal characterized by a plateau of elevated Ca2+, or baseline oscillation that is dependent on extracellular Ca2+ influx.19 The interaction between angiotensin type 2 (AT2) and B2 receptors is discussed by Izumi and Iwao elsewhere in this volume. Several studies have also suggested interaction between the angiotensin type 1 (AT1) and B2 receptors, although others have found no evidence for this interaction.15 There is evidence that the B2 receptor also interacts with ACE.19 Initial evidence for this interaction came from studies showing that ACE inhibitors potentiate the effects of B2 receptor agonists that are resistant to cleavage by ACE. Furthermore, ACE inhibitors reactivate the B2 receptor after desensitization and prevent sequestration of the B2 receptor to caveolae, and there is evidence for the direct association of the B2 receptor and ACE in the cell membrane.19
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In addition to activation by kinin peptides, the B2 receptor may be directly activated by serine proteases such as kallikreins by a mechanism that involves receptor proteolysis.6
BIOLOGICAL ACTIONS WITHIN THE CARDIOVASCULAR SYSTEM The role of kinins in amphibia is described by Conlon, and in the lung by Couture, in this volume. Kinins are potent vasodilators and also promote diuresis and natriuresis. Most of the circulatory effects of kinins are determined by the stimulation of endothelial cells with subsequent endothelial release of nitric oxide and prostacyclin, which diffuse to the vascular smooth muscle causing vasodilatation.19 Evidence for a role for kinins in the regulation of vascular tone and blood pressure in man has come from the studies of the effects of the B2 receptor antagonist icatibant. Icatibant caused coronary artery vasoconstriction, suggesting a role for basal kinin levels in the control of coronary vascular tone.5 Moreover, icatibant attenuated the hypotensive effects of ACE inhibition in normotensive and hypertensive patients.5 BK-(1-5) has antithrombin activity.16 However, it is unlikely that endogenous BK-(1-5) levels inhibit thrombin in vivo because plasma BK-(1-5) levels (30–40 pmol/L) are at least 6 orders of magnitude below the micromolar concentrations required to inhibit thrombin.16
Contact System The “contact system” comprises HMWK complexed with plasma prekallikrein, Hageman factor (XII, FXII), and FXI. It is so called because its components require contact with artificial, negatively charged surfaces for zymogen activation in vitro (Fig. 5).17 In vivo, the contact system is assembled on endothelial and neutrophil cell membranes where it may participate in basal kinin peptide production. This complex associates with endothelial membranes through a binding site formed by the 33 kDa cell-surface receptor for the first component of complement (gC1qR/p33), urokinase plasminogen activator receptor, and cytokeratin.4 Endothelial prolylcarboxypeptidase and/or heat-shock protein 90 initiates the reciprocal activation of plasma prekallikrein to kallikrein, FXII to FXIIa, and FXI to FXIa. Plasma kallikrein, FXIIa, and FXIa all cleave HMWK to release bradykinin. FXIIa also activates plasminogen to plasmin. Plasmin cleaves HMWK to release bradykinin that may contribute to the angioedema that occurs with administration of recombinant tissue plasminogen activator. In addition, plasma prekallikrein may cleave HMWK directly.17 C1 esterase inhibitor plays a critical role in the control of bradykinin production by inhibiting plasma kallikrein, FXIIa, FXIa, and plasmin (Fig. 5). Thus, C1 esterase inhibitor deficiency leads
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Complement activation
C4
C2 C1
FXI
Microbial surface (mannose-binding lectin associated serine proteases)
c
C4b2a
Immune complex
aC1(C1q,C1s,C1r)
c
bradykinin metabolites
plasminogen
FXIIf FXIa
ACE
plasmin FXIIa
c
pl-kallikrein
c
bradykinin
reciprocal activation FXIa
c HMWK
FXI
FXII
bradykinin
c
pl-prekallikrein
HMWK
HMWK
prolylcarboxypeptidase
heat shock protein 90
endothelial cells
NO PGI2 ROS tPA
FIGURE 5 Outline of the contact system and its relationship to the complement pathway, which contributes to angioneurotic edema. The black rectangles indicate enzymes inhibited by C1 esterase inhibitor. The contact system comprises high-molecular-weight kininogen (HMWK) complexed with plasma prekallikrein (pl-prekallikrein), Hageman factor (factor XII, FXII), and FXI. This complex associates with endothelial membranes, where endothelial prolylcarboxypeptidase and/or heat-shock protein 90 initiates the reciprocal activation of prekallikrein to kallikrein, FXII to FXIIa, and FXI to FXIa. Kallikrein, FXIIa, and FXIa can all cleave HMWK to release bradykinin. FXIIa also activates plasminogen to plasmin and plasmin cleaves HMWK to release bradykinin. Not shown in this figure is the role of plasma kallikrein and plasmin in the conversion of FXIIa to FXII fragment (FXIIf). FXIIf activates the first component of the complement cascade (C1) that subsequently cleaves C2 and C4. Bradykinin stimulates endothelial cell B2 receptors to cause the release of nitric oxide (NO), prostacyclin (PGI2), reactive oxygen species (ROS), and tissue-type plasminogen activator (tPA), which together lead to increased vascular permeability and angioedema. The complement pathway is also activated by the classical pathway (immune complex), and the lectin pathway (microbial surface, mannose-binding lectin pathway). Activation of any of these pathways leads to the reduction in C2 and C4 levels. ACE, angiotensin-converting enzyme.
to increased bradykinin formation, particularly during conditions that increase the activity of the contact system, such as tissue trauma. In addition to kinin peptide formation, the contact system activates the intrinsic coagulation, complement, and fibrinolytic systems. Moreover, kinin-mediated stimulation of endothelial release of tissue-type plasminogen activator further promotes fibrinolysis. Tissue prokallikrein may also participate in the contact system by binding to HMWK.6 Activation of the contact system and kinin peptide formation occurs in cardiopulmonary bypass, whereby both bradykinin and kallidin peptides are increased, indicating activation of both plasma prekallikrein and tissue prokallikrein.8
Genetic Models of Deficiency of Components of the Kallikrein–Kinin System Detection of kininogen-deficient human subjects is based on their severe abnormality in surface-activated intrinsic coagulation, fibrinolytic and kinin-generating pathways,
although they have little or no bleeding abnormality.5 Kininogen deficiency in humans is reported to be relatively asymptomatic, suggesting that kinin peptides may have little role in normal physiology. However, studies in experimental animals provide evidence for an important role for kinin peptides in the regulation of blood pressure and sodium homeostasis, and in contributing to inflammatory processes.5 The kininogen-deficient Brown–Norway Katholiek strain of rat shows increased sensitivity to the pressor effects of increased dietary salt, mineralocorticoid administration, and angiotensin II infusion, and an impairment of the cardioprotective effects of preconditioning.5 In addition, the Brown–Norway Katholiek rat shows a reduced response to inflammatory stimuli.5 Gene knockout mouse models have also helped demonstrate the role of the KKS in normal physiology and in disease states. There is some controversy about the effects of B2 receptor gene knockout on blood pressure and cardiac function.22 However, the B2 receptor gene knockout mouse has an exaggerated pressor response to angiotensin II infusion and chronic dietary salt loading, and a diminished cardioprotective
SECTION | XIV Handbook of Biologically Active Peptides: Cardiovascular Peptides
response to ACE inhibitor and AT1 receptor blocker (ARB) therapies, indicating an important role for endogenous kinins in mediating the effects of these therapeutic agents. B2 receptor gene knockout mice have reduced insulin sensitivity despite the increased B1 receptor expression in this model.19 B2 receptor gene knockout mice also have less efficient myocardial metabolism with increased propensity to ischemic myocardial injury and increased cardiac oxygen consumption.22 In addition, B2 receptor gene knockout mice demonstrate increased urinary concentration in response to vasopressin, indicating that endogenous kinins acting through B2 receptors oppose the antidiuretic effect of vasopressin. Studies of the tissue kallikrein gene knockout mouse suggest that tissue kallikrein is the major kinin-forming enzyme in most organs, including the heart and blood vessels, and have identified a role for tissue kallikrein and kinins in protection from acute cardiac ischemia and postischemic cardiac failure, and a nephroprotective role for tissue kallikrein in diabetes.28 However, in contrast to the nephroprotective role of tissue kallikrein, targeted deletion of the B2 receptor protects against the development of diabetic nephropathy, thereby suggesting that the B2 receptor contributes to the pathogenesis of diabetic nephropathy.33 In a direct comparison of B2 receptor and tissue kallikrein gene knockout mice, both models had similar blood pressures to wild-type mice and displayed normal hemodynamic and echocardiographic parameters.34 However, the heart rate was lower in B2 receptor gene knockout mice than in tissue kallikrein gene knockout or wild-type mice. In addition, B2 receptor gene knockout mice, but not tissue kallikrein gene knockout mice, exhibited lower coronary and renal blood flows and greater corresponding vascular resistances than did wild-type mice, indicating a tonic physiological vasodilating effect of bradykinin in these vascular beds. However, maximal coronary vasodilator capacity, estimated after dipyridamole infusion, was similar in the 3 groups of mice. B2 receptor gene knockout mice were significantly more sensitive than were tissue kallikrein gene knockout mice to the vasoconstrictor effects of angiotensin II and norepinephrine. Moreover, renin mRNA levels were significantly higher in B2 receptor gene knockout mice and lower in tissue kallikrein gene knockout mice, compared with that of wild-type mice. Taken together, these results indicate that under basal conditions, the B2 receptor is not an important determinant of blood pressure in mice but is involved in the control of regional vascular tone in the heart and kidney.34 The phenotypic differences observed between B2 receptor and tissue kallikrein gene knockout mice may represent the contribution of plasma kallikrein to bradykinin production and/or B1 receptor activation. Given the vascular and renal actions of kinin peptides, reduced KKS activity has long been a candidate mechanism for essential hypertension.21 However, heterozygous
1391
individuals with a loss of function polymorphism (R53H) of the Klk1 gene have normal blood pressure, although they have an alteration of the geometry of the brachial artery. Moreover, although the R53H polymorphism was associated with reduced plasma and urinary levels of tissue kallikrein, it was not associated with alteration in urinary kallidin levels.2 Gene knockout models also indicate an important role for bradykinin in inflammation and nociception. The B1 receptor gene knockout mouse has a reduced hypotensive response to bacterial lipopolysaccharide and reduced accumulation of polymorphonuclear leukocytes in carrageenan-induced inflammation, although accumulation of mononuclear cells and endothelial permeabilization are preserved.5 By contrast, the B2 receptor gene knockout mouse has reduced paw edema in response to intraplantar injection of carrageenan.5 Moreover, both the B1 and B2 receptor gene knockout mice show evidence of reduced nociception, indicating an important role for endogenous kinins in perception of pain.5
PATHOPHYSIOLOGICAL IMPLICATIONS As noted above, the B2 receptor is constitutively expressed, whereas the B1 receptor is not detectable but is induced by a variety of pathological conditions, including inflammation, toxins, cytokines, and tissue trauma.19,22 Kinin peptides are well recognized for producing cardioprotection mediated by the B2 receptor, as indicated by the prevention of cardioprotection by icatibant.22 Cardioprotection mediated by the B2 receptor includes ischemic preconditioning, the reduction in myocardial infarct size, and the reduction of cardiac hypertrophy and cardiac remodeling post myocardial infarction.19 Kinins protect against ischemia–reperfusion injury by decreasing endothelial adherence of leukocytes, leading to attenuation of post-ischemic leukocyte adherence and disruption of the microvascular barrier, and reduced tissue injury.3 Both the B1 and B2 receptors are implicated in ischemia-induced angiogenesis.19,31 In addition to their induction by inflammation, toxins, cytokines, and tissue trauma, B1 receptors are induced and upregulated by disturbances in circulatory homeostasis, such as induction of experimental hypertension by salt loading, renal artery clipping, or exogenous angiotensin II infusion, as well as by the normal aging process. But the most important stimulus causing overexpression of the B1 receptor was found to be the disruption of the B2 receptor, whether it was due to functional inactivation via a selective B2 receptor antagonist or to the deletion of the B2 receptor gene. In such cases, the B1 receptor can take over some of the vasodilatory functions of the B2 receptor, but not its metabolic (insulin-sensitizing) function. Patients with end stage cardiac failure have increased cardiac B1 receptor
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mRNA and protein levels, in contrast to B2 receptor mRNA and protein levels, which are significantly downregulated.22 It is unclear whether the upregulation of the B1 receptor in patients with heart failure contributes to tissue protection by enhancing regional blood flow, or has a detrimental effect by interacting with inflammatory mediators and further exacerbating the inflammatory process.22 Both ACE inhibitor and ARB therapies increase kinin peptide levels5,10 that may contribute to the therapeutic effects of these agents. Recently, the renin inhibitor aliskiren was shown to increase bradykinin levels in the heart and lung of the rat, associated with increases in tissue kallikrein mRNA and protein levels.11 Studies with tissue kallikrein gene knockout mice confirm the role of the KKS in mediating cardioprotection by ACE inhibitor and ARB therapies.28 The importance of the B2 receptor in mediating in part the benefits of ACE inhibitor and ARB therapies is illustrated by the effects of icatibant, which attenuates the hypotensive effects of ACE inhibition in humans,5 and also attenuates angiogenesis and reduction of cardiac hypertrophy, infarct size, and fibrosis produced by these therapies in animal models. The B2 receptor is also implicated in the improvement in ischemic preconditioning, and in insulin sensitivity, reported with ACE inhibition.19,22 By contrast, treatment with a selective B1 receptor antagonist in the setting of myocardial infarction did not modify myocardial infarct size, but reversed the cardioprotective effects of ARB therapy, an effect attributed to cross-talk between the AT1 and B1 receptors.22 Both the B1 and B2 receptors are implicated in the promotion of angiogenesis by ACE inhibition.19,31 The potential for the KKS to contribute to inflammation is well illustrated by the clinical condition of angioneurotic edema, whereby C1 esterase inhibitor deficiency results in unpredictable activation of the contact system, leading to angioedema and increased circulating bradykinin levels (Fig. 5).5 The role of kinins in angioneurotic edema is demonstrated by the therapeutic benefits of icatibant and plasma kallikrein inhibition.17 Local tissue trauma and sepsis produce local kallikrein activation, possibly involving the contact system, and kinins contribute to the cardinal features of inflammation, producing vasodilatation, increased blood flow, vascular permeability, edema, neutrophil chemotaxis, and pain.3 Increased kinin peptide levels may contribute to the increased incidence of angioedema associated with ACE inhibitor and ARB therapies.5,10 Kinin levels are increased further when neutral endopeptidase 24.11 (NEP) inhibition is combined with ACE inhibition. Consequently, the incidence of angioedema is higher with combined ACE and NEP inhibition than with ACE inhibition alone.7 Moreover, reduced plasma levels of aminopeptidase P are associated with ACE inhibitor-induced angioedema.1 Patients with heart failure have reduced circulating levels of bradykinin
and kallidin peptides5 that may account for the lower incidence of angioedema in subjects with heart failure treated with ACE inhibitors or vasopeptidase inhibitors.7 In summary, kinin peptides exert a broad range of cardioprotective and inflammatory actions. In general, low physiological levels of kinin peptides play an important role in cardiovascular homeostasis, particularly in relation to sodium homeostasis and in cardioprotection, whereas the high pathological levels of kinin peptides that occur when the contact system is activated and may also occur when key kininase enzymes such as ACE, NEP and aminopeptidase P are inhibited, contribute to inflammation.
ACKNOWLEDGMENTS Duncan Campbell (Grant ID 395508) is a recipient of a Senior Research Fellowship from the National Health and Medical Research Council of Australia. This work was supported partly by the Victorian Government’s Operational Infrastructure Support Program.
REFERENCES 1. Adam A, Cugno M, Molinaro G, Perez M, Lepage Y, Agostoni A. Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors. Lancet 2002;359:2088–9. 2. Azizi M, Emanueli C, Peyrard S, Maddedu P, Alhenc-Gelas F, Campbell DJ. Genetic and dietary control of plasma tissue kallikrein secretion and urinary kinins excretion in man. J Hypertens 2008;26:714–20. 3. Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992;44:1–80. 4. Bossi F, Peerschke EI, Ghebrehiwet B, Tedesco F. Cross-talk between the complement and the kinin system in vascular permeability. Immunol Lett 2011;140:7–13. 5. Campbell DJ. The kallikrein–kinin system in humans. Clin Exp Pharmacol Physiol 2001;28:1060–5. 6. Campbell DJ. The renin –angiotensin and the kallikrein–kinin systems. Int J Biochem Cell Biol 2003;35:784–91. 7. Campbell DJ. Vasopeptidase inhibition: a double-edged sword? Hypertension 2003;41:383–9. 8. Campbell DJ, Dixon B, Kladis A, Kemme M, Santamaria JD. Activation of the kallikrein–kinin system by cardiopulmonary bypass in humans. Am J Physiol Regul Integr Comp Physiol 2001;281:R1059–70. 9. Campbell DJ, Kladis A, Duncan A-M. Bradykinin peptides in kidney, blood, and other tissues of the rat. Hypertension 1993;21:155–65. 10. Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation 2005;111:315–20. 11. Campbell DJ, Zhang Y, Kelly DJ, Gilbert RE, McCarthy DJ, Shi W, et al. Aliskiren increases bradykinin and tissue kallikrein mRNA levels in the heart. Clin Exp Pharmacol Physiol 2011;38:623–31. 12. Clements JA, Willemsen NM, Myers SA, Dong Y. The tissue kallikrein family of serine proteases: functional roles in human disease and potential as clinical biomarkers. Crit Rev Clin Lab Sci 2004;41:265–312. 13. Elliot DF, Lewis GP, Horton EW. The structure of bradykinin – a plasma kinin from ox blood. Biochem Biophys Res Commun 1960;3:87–91.
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14. Furuto-Kato S, Matsumoto A, Kitamura N, Nakanishi S. Primary structures of the mRNAs encoding the rat precursors for bradykinin and T-kinin. Structural relationship of kininogens with major acute phase protein and a1-cysteine proteinase inhibitor. J Biol Chem 1985;260:12054–9. 15. Hansen JL, Hansen JT, Speerschneider T, Lyngso C, Erikstrup N, Burstein ES, et al. Lack of evidence for AT1R/B2R heterodimerization in COS-7, HEK293, and NIH3T3 cells: how common is the AT1R/ B2R heterodimer? J Biol Chem 2009;284:1831–9. 16. Hasan AAK, Amenta S, Schmaier AH. Bradykinin and its metabolite, Arg-Pro-Pro-Gly. Phe, are selective inhibitors of a-thrombin-induced platelet activation. Circulation 1996;94:517–28. 17. Kaplan AP, Ghebrehiwet B. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010;47:2161–9. 18. Kitamura N, Kitagawa H, Fukushima D, Takagaki Y, Miyata T, Nakanishi S. Structural organization of the human kininogen gene and a model for its evolution. J Biol Chem 1985;260:8610–7. 19. Leeb-Lundberg LM, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL. International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 2005;57:27–77. 20. Lundwall A, Band V, Blaber M, Clements JA, Courty Y, Diamandis EP, et al. A comprehensive nomenclature for serine proteases with homology to tissue kallikreins. Biol Chem 2006;387:637–41. 21. Madeddu P, Emanueli C, El-Dahr S. Mechanisms of disease: the tissue kallikrein–kinin system in hypertension and vascular remodeling. Nat Clin Pract Nephrol 2007;3:208–21. 22. Manolis AJ, Marketou ME, Gavras I, Gavras H. Cardioprotective properties of bradykinin: role of the B2 receptor. Hypertens Res 2010;33:772–7. 23. Murphey LJ, Eccles WK, Williams GH, Brown NJ. Loss of sodium modulation of plasma kinins in human hypertension. J Pharmacol Exp Ther 2004;308:1046–52. 24. Neth P, Arnhold M, Nitschko H, Fink E. The mRNAs of prekallikrein, factors XI and XII, and kininogen, components of the contact phase cascade are differentially expressed in multiple non-hepatic human tissues. Thromb Haemost 2001;85:1043–7.
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25. Nolly H, Carbini LA, Scicli G, Carretero OA, Scicli AG. A local kallikrein-kinin system is present in rat hearts. Hypertension 1994;23:919–23. 26. Nolly H, Saed G, Carretero OA, Scicli G, Scicli AG. Adrenal kallikrein. Hypertension 1993;21:911–5. 27. Pierce JV, Webster ME. Human plasma kallidin: isolation and chemical studies. Biochem Biophys Res Commun 1961;5:353–7. 28. Pizard A, Richer C, Bouby N, Picard N, Meneton P, Azizi M, et al. Genetic deficiency in tissue kallikrein activity in mouse and man: effect on arteries, heart and kidney. Biol Chem 2008;389:701–6. 29. Regoli D, Rhaleb N-E, Drapeau G, Dion S, Tousignant C, D’OrléansJuste P, et al. Basic pharmacology of kinins: pharmacologic receptors and other mechanisms. Adv Exp Med Biol 1989;247A:399–407. 30. Roche e Silva M, Beraldo WT, Rosenfeld G. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am J Physiol 1949;156:261–73. 31. Sanchez de Miguel L, Neysari S, Jakob S, Petrimpol M, Butz N, Banfi A, et al. B2-kinin receptor plays a key role in B1-, angiotensin converting enzyme inhibitor-, and vascular endothelial growth factor- stimulated in vitro angiogenesis in the hypoxic mouse heart. Cardiovasc Res 2008;80:106–13. 32. Takagaki Y, Kitamura N, Nakanishi S. Cloning and sequence analysis of cDNAs for human high molecular weight and low molecular weight prekininogens. Primary structures of two human prekininogens. J Biol Chem 1985;260:8601–9. 33. Tan Y, Keum JS, Wang B, McHenry MB, Lipsitz SR, Jaffa AA. Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy. Am J Physiol Renal Physiol 2007;293: F1026–35. 34. Trabold F, Pons S, Hagege AA, Bloch-Faure M, Alhenc-Gelas F, Giudicelli JF, et al. Cardiovascular phenotypes of kinin B2 receptorand tissue kallikrein-deficient mice. Hypertension 2002;40:90–5. 35. Werle E. Discovery of the most important kallikreins and kallikrein inhibitors. In: Erdos EG, editor. Handbook of experimental pharmacology, vol. 25. Bradykinin, kallidin and kallikrein. Berlin: SpringerVerlag; 1970. p. 1–6.
Bradykinin Peptides Duncan John Campbell
ABSTRACT The kallikrein–kinin system (KKS) generates a family of bioactive peptides with varying biological activities. These include hydroxylated and nonhydroxylated bradykinin and kallidin (Lys0-bradykinin) peptides and their respective carboxypeptidase metabolites, des-Arg9-bradykinin and des-Arg10-kallidin. Although bradykinin and kallidin act mainly via the bradykinin type 2 (B2) receptor, des-Arg9-bradykinin and des-Arg10-kallidin act mainly via the bradykinin type 1 (B1) receptor. Kinins are potent vasodilators, promote natriuresis and diuresis, and have beneficial cardiovascular effects; however, kinins may also promote inflammation. Peptidases are important determinants of kinin levels, and increased kinin levels may contribute to both the beneficial and adverse effects of peptidase inhibitor therapy.
DISCOVERY Bradykinin and its related peptides are generated by the action of kallikrein enzymes on kininogen substrates. Initial discoveries of the kallikrein–kinin system (KKS) took place in the laboratories of Frey and Kraut in Germany (reviewed by Werle35) and Roche e Silva in Brazil.30 In the laboratory of Frey and Kraut, kallikrein-like activity was initially revealed by the hypotensive effects of intravenous injection of urine.35 It was also found that plasma and serum deactivate this activity. Subsequent isolation of this hypotensive material in large amounts from the pancreas led to it being named kallikrein, although it was evident that the pancreas was not the only source of kallikrein. Kallikrein could be extracted from the pancreas in both the active and inactive forms. A similar hypotensive material was also isolated from plasma in both the active and inactive forms and was named plasma kallikrein. Moreover, the inactive forms of kallikrein were activated by trypsin. The biological activity of kallikrein extracted from the submandibular salivary gland was found to be due to its enzymatic release of a low-molecular-weight, thermostable compound from a serum protein. This low-molecular-weight compound, 1386
believed to be a polypeptide, was initially called DK, and later called kallidin, and its inactive precursor was called kallidinogen.35 In the laboratory of Roche e Silva, bradykinin was initially identified as a hypotensive and smooth musclestimulating factor released from plasma globulin by snake venoms and by trypsin.30 It was named bradykinin because it produced a slow contraction of the guinea pig ileum.30 Trypsin digestion of an ammonium sulfate fraction from ox serum produced the nonapeptide bradykinin, the sequence of which was reported by Elliott et al. in 1960.13 However, digestion of human plasma with human urinary kallikrein produced two peaks of bioactivity, one (named kallidin I) corresponding to bradykinin and a second (named kallidin II) that corresponded to lysine bradykinin.27 Because human urinary kallikrein can hydrolyze synthetic arginine esters but not lysine esters, Pierce and Webster concluded that human urinary kallikrein produced lysine bradykinin (now known as kallidin).27
STRUCTURE OF KININOGEN mRNA AND GENE Kininogens are glycoproteins that contain the bradykinin sequence in their midportion. There are two forms of kininogen that differ in structure, size, and susceptibility to cleavage by plasma and tissue kallikreins.3 Human highmolecular-weight kininogen (HMWK) has 626 amino acids, with a mass of 88–120 kDa, whereas human low-molecularweight kininogen (LMWK) has 409 amino acids, with a mass of 50–68 kDa.32 The human kininogen gene encompasses 11 exons spanning approximately 27 kb and codes for both HMWK and LMWK by differential splicing of the initial messenger RNA (mRNA) transcript (Fig. 1).18,32 In the rat, T-kininogen (major acute phase protein) is a potential precursor for Ile,Ser-bradykinin and Met,Ile,Ser-bradykinin.14 However, there is no evidence that T-kininogen is a precursor of kinin peptides in vivo.9 Handbook of Biologically Active Peptides. http://dx.doi.org/10.1016/B978-0-12-385095-9.00188-3 Copyright © 2013 Elsevier Inc. All rights reserved.
SECTION | XIV Handbook of Biologically Active Peptides: Cardiovascular Peptides
Kininogen gene
Kininogen gene 10BK
Exons 1-9
1387
10HMW
11
LMWK
HMWK
Tissue kallikrein LMWK mRNA Exons 1-9
10BK
10HMW
poly A
poly A
LMWK Heavy chain BK Light chain 362 aa 9 aa 38 aa
hydroxylated
Plasma kallikrein
HMWK mRNA
Exons 1-9 10BK 11
Nonhydroxylated
Aminopeptidase Kallidin KBK-(1-9) Hyp3-KBK-(1-9)
Bradykinin BK-(1-9) Hyp3-BK-(1-9)
HMWK Heavy chain 362 aa
BK 9 aa
Light chain 255 aa
FIGURE 1 Diagrammatic representation of differential splicing of the kininogen gene transcript that produces high-molecular-weight kininogen (HMWK) and low-molecular-weight kininogen (LMWK) mRNA. HMWK represents exons 1–9 spliced to the whole of exon 10, whereas LMWK represents exons 1–9 and the first 78 base pairs of exon 10 spliced to exon 11.18,32 Both HMWK and LMWK contain the bradykinin (BK) sequence in their midportion, between their respective heavy and light chains. aa, amino acid. Not drawn to scale.
PROCESSING OF THE PRECURSOR Bradykinin and kallidin are released from kininogens predominantly by the action of the serine proteases plasma kallikrein and tissue kallikrein. Plasma kallikrein is initially secreted as the inactive prekallikrein, and tissue kallikrein is initially secreted as inactive prokallikrein. Both plasma prekallikrein and tissue prokallikrein are activated by serine protease activity. Although a single gene codes for plasma prekallikrein, there is a large family of tissue prokallikrein genes that code for tissue-kallikrein-like serine proteases. In humans, Klk1 codes for true tissue kallikrein, the only member of the tissuekallikrein-like family of serine proteases known to generate kinin peptides.20 However, in rats, true tissue kallikrein is referred to as Klk1b3, although Lundwall et al. recommended that this sequence be given the gene symbol Klk1.20 In humans, plasma kallikrein forms bradykinin from HMWK, whereas tissue kallikrein forms kallidin from HMWK and LMWK (Figs 2 and 3). By contrast, both plasma and tissue kallikrein generate bradykinin in rodents.3,5 In humans, a proportion of kininogens are hydroxylated on Pro3 of the bradykinin sequence, leading to the formation of hydroxylated kinin peptides (Hyp3-bradykinin and Hyp4kallidin). Hydroxylated kinins have biological activities that are similar to those of nonhydroxylated kinins.29 Alternative pathways of kinin formation involving enzymes other than kallikreins may operate in disease states.5 Although LMWK is a poor substrate for plasma kallikrein, cleavage by neutrophil elastase renders it much more susceptible to cleavage by plasma kallikrein to release bradykinin. Moreover, the combination of mast cell tryptase and neutrophil elastase releases bradykinin from oxidized kininogens that are resistant to cleavage by kallikreins.
Carboxypeptidase
Carboxypeptidase B2 receptor
KBK-(1-8) Hyp3-KBK-(1-8)
Aminopeptidase
BK-(1-8) Hyp3-BK-(1-8)
B1 receptor
FIGURE 2 Overview of the kallikrein–kinin system in humans. LMWK, low-molecular-weight kininogen; HMWK, high-molecular-weight kininogen; Hyp, hydroxyproline. A proportion of kininogen is hydroxylated on the third amino acid (Hyp3) of the bradykinin sequence of the precursor. Thus, bradykinin peptides may be nonhydroxylated [BK-(1-9)] or hydroxylated [Hyp3-BK-(1-9)]. Kallidin is Lys0-bradykinin and may also be either non-hydroxylated [KBK-(1-9)] or hydroxylated [Hyp3-KBK-(1-9)]. Similarly, the carboxypeptidase metabolites des-Arg9-BK-(1-9) and desArg9-KBK-(1-9) may also be either non-hydroxylated [BK-(1-8), KBK(1-8)] or hydroxylated [Hyp3-BK-(1-8), Hyp3-KBK-(1-8)]. Tissue kallikrein Plasma kallikrein HMW & LMW kininogen -Ser-Leu-Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Ser-Ser-Leu-Met-Lys-Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg-Ser0 1 2 3 4 5 6 7 8 9 B2 receptor agonists Bradykinin [BK-(1-9)] Kallidin [KBK-(1-9)] Hyp3-BK-(1-9) Hyp3-KBK-(1-9) B1 receptor agonists Bradykinin [BK-(1-8)] Kallidin [KBK-(1-8)] Hyp3-BK-(1-8) Hyp3-KBK-(1-8)
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg Lys-Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe Lys-Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe
FIGURE 3 Amino acid sequences of the agonists of the type 1 (B1) and type 2 (B2) bradykinin receptors. Hyp, hydroxyproline. Bradykinin [BK-(19)] and kallidin [Lys0-bradykinin, KBK-(1-9)] are excised from the interior of the kininogen molecules. Tissue kallikrein cleaves both HMWK and LMWK between Met379 and Lys380 (the same numbering for human HMWK and LMWK precursors) to produce the amino-terminus and between Arg389 and Ser390 to produce the carboxy-terminus of kallidin. Plasma kallikrein cleaves HMWK between Lys380 and Arg381 to produce the amino-terminus and between Arg389 and Ser390 to produce the carboxy-terminus of bradykinin.
Chapter | 188 Bradykinin Peptides
1388
Endopeptidase 24.15
Angiotensin converting enzyme
TABLE 1 Blood Kinin Peptide Levels in Humans
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Aminopeptidase P Dipeptidyl peptidase IV
Endopeptidase 24.11
Prolylendopeptidase
Carboxypeptidase N Carboxypeptidase M Endothelin converting enzyme
FIGURE 4 Metabolism of bradykinin. Carboxypeptidase N is known as kininase I and angiotensin-converting enzyme is also known as kininase II. Carboxypeptidases M and N produce sequential cleavage of amino acids from the carboxy-terminus of the peptide. Aminopeptidase P produces sequential cleavage of amino acids from the amino-terminus of the peptide. Angiotensin-converting enzyme is a carboxy dipeptidase that produces sequential cleavage of dipeptides from the carboxy-terminus of the peptide. Dipeptidyl peptidase IV cleaves des-Arg1-bradykinin.
Kinin production in vivo is controlled partly by endogenous inhibitors of the kallikrein enzymes. The main inhibitors of plasma kallikrein are C1 esterase inhibitor, α2-macroglobulin, and antithrombin III.3 An important inhibitor of tissue kallikrein is kallistatin, although there is continuing uncertainty about the function of kallistatin in vivo.5 Kinin peptide metabolism is an important determinant of kinin levels in blood and tissue. Many different peptidases participate in the conversion of bradykinin and kallidin to alternative bioactive peptides and their degradation (Fig. 4). Aminopeptidase-mediated cleavage of kallidin generates bradykinin. Carboxypeptidase (kininase I)-mediated cleavage converts bradykinin and kallidin, which are more potent on the type 2 (B2) bradykinin receptor, to des-Arg9-bradykinin and des-Arg10-kallidin, respectively, which are also bioactive and more potent on the type 1 (B1) receptor (Fig. 2).29 Thus, there are 8 bioactive kinin peptides in humans, hydroxylated and nonhydroxylated bradykinin and kallidin peptides, and their carboxypeptidase metabolites (Fig. 3). Angiotensin-converting enzyme (ACE) plays an important role in bradykinin metabolism, producing bradykinin-(1-5) [BK-(1-5)], the most abundant bradykinin metabolite,23 by sequential cleavage of dipeptides from the carboxy-terminus of bradykinin. Other peptidases play a greater role in kinin peptide metabolism during ACE inhibition.
DISTRIBUTION OF KININOGEN AND KALLIKREIN mRNA, AND KININ PEPTIDES The liver is the main site of kininogen production and, in humans, HMWK mRNA is also found in the kidney, pancreas, placenta, heart, and colon, whereas LMWK mRNA is found in the kidney, brain, placenta, testis, pancreas, thymus, heart, spleen, lung, colon, and small intestine.24 Plasma prekallikrein mRNA is present in all tissues examined and is most abundantly present in the liver and
Peptide (fmol/mL)
Placebo
BK-(1-7)
1.4 (0.5–4.3)
BK-(1-8)
0.08 (0.02–0.41)
BK-(1-9)
0.18 (0.02–1.90)
Hyp3-BK-(1-7)
<0.14
Hyp3-BK-(1-8)
0.53 (0.12–2.37)
Hyp3-BK-(1-9)
0.18 (0.04–0.91)
KBK-(1-7)
0.46 (0.07–3.33)
KBK-(1-8)
0.10 (0.01–1.35)
KBK-(1-9)
0.22 (0.02–2.70)
Hyp3-KBK-(1-7)
0.04 (0.01–0.49)
Hyp3-KBK-(1-8)
<0.03
Hyp3-KBK-(1-9)
0.04 (0.01–0.26)
Data shown as geometric mean (95% confidence interval), n = 19 for bradykinin (BK) peptides; n = 18 for kallidin (KBK) peptides. Hyp, hydroxyproline. Data from Campbell et al.10
pancreas.24 In humans, the Klk1 gene is highly expressed in the kidney, pancreas, salivary gland, endometrium, ovary, skin, and pituitary.12 Other sites of Klk1 gene expression include the colon, heart, blood vessels, and adrenal.25,26,28 Bradykinin peptides are present in all tissues studied (blood, heart, aorta, brown adipose tissue, adrenal, lung, and brain).9 In humans, circulating levels of kinin peptides are low, usually <3 fmol/mL (Table 1). Studies in rats show that the levels of bradykinin in tissues are higher than in blood,9 and in humans, bradykinin and kallidin peptide levels are higher in venous than in arterial blood,5 consistent with the tissue being the main site of formation of these peptides. Bradykinin peptides are more abundant than kallidin peptides in the blood and atrial tissue of humans.5,10 In human urine, kallidin peptides are more abundant than bradykinin peptides, and the levels are several orders of magnitude higher than that in blood.5
RECEPTORS AND SIGNALING CASCADES In the basal state, the B2 receptor is constitutively expressed throughout and mediates the majority of the vascular and metabolic actions of kinins, whereas the B1 receptor is not detectable but is induced by a variety of pathological conditions, including inflammation, toxins, cytokines, and tissue trauma.19,22 Both B1 and B2 receptors can be expressed by the same cell types: vascular endothelial and smooth muscle cells, nonvascular smooth muscle such as the uterus and
SECTION | XIV Handbook of Biologically Active Peptides: Cardiovascular Peptides
intestine, fibroblasts, epithelial cells, various tumor cells, and also on leukocytes and in the central nervous system.19 Immunohistochemical studies show a different distribution of B2 receptors in arteries and arterioles. B2 receptors are predominant in the endothelium of arteries with minor immunohistochemical staining in smooth muscle cells, whereas there is intense staining of the tunic media and minor staining of the endothelium of arterioles.5 The pharmacology of kinin receptors has been reviewed by Leeb-Lundberg et al.19 The B1 and B2 receptors are G protein-coupled, 7-transmembrane-spanning receptors. The B2 receptor signals through Gαq, and also interacts with Gαs and Gαq12/13. Stimulation of the Gαq-sensitive phospholipase Cß produces phosphoinositol hydrolysis and increased intracellular free Ca2+. Moreover, translocation of protein kinase C isoenzymes α, ε, and ζ has been observed in fibroblasts and endothelial cells. B2 receptor stimulation can also result in phospholipase A2 and phospholipase D activation.19 These second messenger systems result in stimulation of endothelial nitric oxide synthase and nitric oxide production through Ca2+-mediated mechanisms in endothelial cells, in addition to cellular release of prostacyclin, reactive oxygen species, and tissue-type plasminogen activator. The B1 receptor interacts with Gαq, and Gαi, through which it stimulates many of the same signaling pathways as the B2 receptor, including phosphoinositol hydrolysis, elevation of intracellular free Ca2+, arachidonic acid release, eicosanoid production, endothelial nitric oxide synthase activation, and nitric oxide production. Although they seem to couple to similar cellular signaling pathways, the pattern of signaling of B1 and B2 receptors may differ. In vascular smooth muscle cells, B2 receptor stimulation leads to transient phosphoinositol hydrolysis that exhibits little dependence on extracellular Ca2+, whereas B1 receptor stimulation is more sustained and significantly dependent on extracellular Ca2+. Moreover, the B2 receptor elicits a transient increase in intracellular Ca2+, whereas the B1 receptor elicits a sustained signal characterized by a plateau of elevated Ca2+, or baseline oscillation that is dependent on extracellular Ca2+ influx.19 The interaction between angiotensin type 2 (AT2) and B2 receptors is discussed by Izumi and Iwao elsewhere in this volume. Several studies have also suggested interaction between the angiotensin type 1 (AT1) and B2 receptors, although others have found no evidence for this interaction.15 There is evidence that the B2 receptor also interacts with ACE.19 Initial evidence for this interaction came from studies showing that ACE inhibitors potentiate the effects of B2 receptor agonists that are resistant to cleavage by ACE. Furthermore, ACE inhibitors reactivate the B2 receptor after desensitization and prevent sequestration of the B2 receptor to caveolae, and there is evidence for the direct association of the B2 receptor and ACE in the cell membrane.19
1389
In addition to activation by kinin peptides, the B2 receptor may be directly activated by serine proteases such as kallikreins by a mechanism that involves receptor proteolysis.6
BIOLOGICAL ACTIONS WITHIN THE CARDIOVASCULAR SYSTEM The role of kinins in amphibia is described by Conlon, and in the lung by Couture, in this volume. Kinins are potent vasodilators and also promote diuresis and natriuresis. Most of the circulatory effects of kinins are determined by the stimulation of endothelial cells with subsequent endothelial release of nitric oxide and prostacyclin, which diffuse to the vascular smooth muscle causing vasodilatation.19 Evidence for a role for kinins in the regulation of vascular tone and blood pressure in man has come from the studies of the effects of the B2 receptor antagonist icatibant. Icatibant caused coronary artery vasoconstriction, suggesting a role for basal kinin levels in the control of coronary vascular tone.5 Moreover, icatibant attenuated the hypotensive effects of ACE inhibition in normotensive and hypertensive patients.5 BK-(1-5) has antithrombin activity.16 However, it is unlikely that endogenous BK-(1-5) levels inhibit thrombin in vivo because plasma BK-(1-5) levels (30–40 pmol/L) are at least 6 orders of magnitude below the micromolar concentrations required to inhibit thrombin.16
Contact System The “contact system” comprises HMWK complexed with plasma prekallikrein, Hageman factor (XII, FXII), and FXI. It is so called because its components require contact with artificial, negatively charged surfaces for zymogen activation in vitro (Fig. 5).17 In vivo, the contact system is assembled on endothelial and neutrophil cell membranes where it may participate in basal kinin peptide production. This complex associates with endothelial membranes through a binding site formed by the 33 kDa cell-surface receptor for the first component of complement (gC1qR/p33), urokinase plasminogen activator receptor, and cytokeratin.4 Endothelial prolylcarboxypeptidase and/or heat-shock protein 90 initiates the reciprocal activation of plasma prekallikrein to kallikrein, FXII to FXIIa, and FXI to FXIa. Plasma kallikrein, FXIIa, and FXIa all cleave HMWK to release bradykinin. FXIIa also activates plasminogen to plasmin. Plasmin cleaves HMWK to release bradykinin that may contribute to the angioedema that occurs with administration of recombinant tissue plasminogen activator. In addition, plasma prekallikrein may cleave HMWK directly.17 C1 esterase inhibitor plays a critical role in the control of bradykinin production by inhibiting plasma kallikrein, FXIIa, FXIa, and plasmin (Fig. 5). Thus, C1 esterase inhibitor deficiency leads
Chapter | 188 Bradykinin Peptides
1390
Complement activation
C4
C2 C1
FXI
Microbial surface (mannose-binding lectin associated serine proteases)
c
C4b2a
Immune complex
aC1(C1q,C1s,C1r)
c
bradykinin metabolites
plasminogen
FXIIf FXIa
ACE
plasmin FXIIa
c
pl-kallikrein
c
bradykinin
reciprocal activation FXIa
c HMWK
FXI
FXII
bradykinin
c
pl-prekallikrein
HMWK
HMWK
prolylcarboxypeptidase
heat shock protein 90
endothelial cells
NO PGI2 ROS tPA
FIGURE 5 Outline of the contact system and its relationship to the complement pathway, which contributes to angioneurotic edema. The black rectangles indicate enzymes inhibited by C1 esterase inhibitor. The contact system comprises high-molecular-weight kininogen (HMWK) complexed with plasma prekallikrein (pl-prekallikrein), Hageman factor (factor XII, FXII), and FXI. This complex associates with endothelial membranes, where endothelial prolylcarboxypeptidase and/or heat-shock protein 90 initiates the reciprocal activation of prekallikrein to kallikrein, FXII to FXIIa, and FXI to FXIa. Kallikrein, FXIIa, and FXIa can all cleave HMWK to release bradykinin. FXIIa also activates plasminogen to plasmin and plasmin cleaves HMWK to release bradykinin. Not shown in this figure is the role of plasma kallikrein and plasmin in the conversion of FXIIa to FXII fragment (FXIIf). FXIIf activates the first component of the complement cascade (C1) that subsequently cleaves C2 and C4. Bradykinin stimulates endothelial cell B2 receptors to cause the release of nitric oxide (NO), prostacyclin (PGI2), reactive oxygen species (ROS), and tissue-type plasminogen activator (tPA), which together lead to increased vascular permeability and angioedema. The complement pathway is also activated by the classical pathway (immune complex), and the lectin pathway (microbial surface, mannose-binding lectin pathway). Activation of any of these pathways leads to the reduction in C2 and C4 levels. ACE, angiotensin-converting enzyme.
to increased bradykinin formation, particularly during conditions that increase the activity of the contact system, such as tissue trauma. In addition to kinin peptide formation, the contact system activates the intrinsic coagulation, complement, and fibrinolytic systems. Moreover, kinin-mediated stimulation of endothelial release of tissue-type plasminogen activator further promotes fibrinolysis. Tissue prokallikrein may also participate in the contact system by binding to HMWK.6 Activation of the contact system and kinin peptide formation occurs in cardiopulmonary bypass, whereby both bradykinin and kallidin peptides are increased, indicating activation of both plasma prekallikrein and tissue prokallikrein.8
Genetic Models of Deficiency of Components of the Kallikrein–Kinin System Detection of kininogen-deficient human subjects is based on their severe abnormality in surface-activated intrinsic coagulation, fibrinolytic and kinin-generating pathways,
although they have little or no bleeding abnormality.5 Kininogen deficiency in humans is reported to be relatively asymptomatic, suggesting that kinin peptides may have little role in normal physiology. However, studies in experimental animals provide evidence for an important role for kinin peptides in the regulation of blood pressure and sodium homeostasis, and in contributing to inflammatory processes.5 The kininogen-deficient Brown–Norway Katholiek strain of rat shows increased sensitivity to the pressor effects of increased dietary salt, mineralocorticoid administration, and angiotensin II infusion, and an impairment of the cardioprotective effects of preconditioning.5 In addition, the Brown–Norway Katholiek rat shows a reduced response to inflammatory stimuli.5 Gene knockout mouse models have also helped demonstrate the role of the KKS in normal physiology and in disease states. There is some controversy about the effects of B2 receptor gene knockout on blood pressure and cardiac function.22 However, the B2 receptor gene knockout mouse has an exaggerated pressor response to angiotensin II infusion and chronic dietary salt loading, and a diminished cardioprotective
SECTION | XIV Handbook of Biologically Active Peptides: Cardiovascular Peptides
response to ACE inhibitor and AT1 receptor blocker (ARB) therapies, indicating an important role for endogenous kinins in mediating the effects of these therapeutic agents. B2 receptor gene knockout mice have reduced insulin sensitivity despite the increased B1 receptor expression in this model.19 B2 receptor gene knockout mice also have less efficient myocardial metabolism with increased propensity to ischemic myocardial injury and increased cardiac oxygen consumption.22 In addition, B2 receptor gene knockout mice demonstrate increased urinary concentration in response to vasopressin, indicating that endogenous kinins acting through B2 receptors oppose the antidiuretic effect of vasopressin. Studies of the tissue kallikrein gene knockout mouse suggest that tissue kallikrein is the major kinin-forming enzyme in most organs, including the heart and blood vessels, and have identified a role for tissue kallikrein and kinins in protection from acute cardiac ischemia and postischemic cardiac failure, and a nephroprotective role for tissue kallikrein in diabetes.28 However, in contrast to the nephroprotective role of tissue kallikrein, targeted deletion of the B2 receptor protects against the development of diabetic nephropathy, thereby suggesting that the B2 receptor contributes to the pathogenesis of diabetic nephropathy.33 In a direct comparison of B2 receptor and tissue kallikrein gene knockout mice, both models had similar blood pressures to wild-type mice and displayed normal hemodynamic and echocardiographic parameters.34 However, the heart rate was lower in B2 receptor gene knockout mice than in tissue kallikrein gene knockout or wild-type mice. In addition, B2 receptor gene knockout mice, but not tissue kallikrein gene knockout mice, exhibited lower coronary and renal blood flows and greater corresponding vascular resistances than did wild-type mice, indicating a tonic physiological vasodilating effect of bradykinin in these vascular beds. However, maximal coronary vasodilator capacity, estimated after dipyridamole infusion, was similar in the 3 groups of mice. B2 receptor gene knockout mice were significantly more sensitive than were tissue kallikrein gene knockout mice to the vasoconstrictor effects of angiotensin II and norepinephrine. Moreover, renin mRNA levels were significantly higher in B2 receptor gene knockout mice and lower in tissue kallikrein gene knockout mice, compared with that of wild-type mice. Taken together, these results indicate that under basal conditions, the B2 receptor is not an important determinant of blood pressure in mice but is involved in the control of regional vascular tone in the heart and kidney.34 The phenotypic differences observed between B2 receptor and tissue kallikrein gene knockout mice may represent the contribution of plasma kallikrein to bradykinin production and/or B1 receptor activation. Given the vascular and renal actions of kinin peptides, reduced KKS activity has long been a candidate mechanism for essential hypertension.21 However, heterozygous
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individuals with a loss of function polymorphism (R53H) of the Klk1 gene have normal blood pressure, although they have an alteration of the geometry of the brachial artery. Moreover, although the R53H polymorphism was associated with reduced plasma and urinary levels of tissue kallikrein, it was not associated with alteration in urinary kallidin levels.2 Gene knockout models also indicate an important role for bradykinin in inflammation and nociception. The B1 receptor gene knockout mouse has a reduced hypotensive response to bacterial lipopolysaccharide and reduced accumulation of polymorphonuclear leukocytes in carrageenan-induced inflammation, although accumulation of mononuclear cells and endothelial permeabilization are preserved.5 By contrast, the B2 receptor gene knockout mouse has reduced paw edema in response to intraplantar injection of carrageenan.5 Moreover, both the B1 and B2 receptor gene knockout mice show evidence of reduced nociception, indicating an important role for endogenous kinins in perception of pain.5
PATHOPHYSIOLOGICAL IMPLICATIONS As noted above, the B2 receptor is constitutively expressed, whereas the B1 receptor is not detectable but is induced by a variety of pathological conditions, including inflammation, toxins, cytokines, and tissue trauma.19,22 Kinin peptides are well recognized for producing cardioprotection mediated by the B2 receptor, as indicated by the prevention of cardioprotection by icatibant.22 Cardioprotection mediated by the B2 receptor includes ischemic preconditioning, the reduction in myocardial infarct size, and the reduction of cardiac hypertrophy and cardiac remodeling post myocardial infarction.19 Kinins protect against ischemia–reperfusion injury by decreasing endothelial adherence of leukocytes, leading to attenuation of post-ischemic leukocyte adherence and disruption of the microvascular barrier, and reduced tissue injury.3 Both the B1 and B2 receptors are implicated in ischemia-induced angiogenesis.19,31 In addition to their induction by inflammation, toxins, cytokines, and tissue trauma, B1 receptors are induced and upregulated by disturbances in circulatory homeostasis, such as induction of experimental hypertension by salt loading, renal artery clipping, or exogenous angiotensin II infusion, as well as by the normal aging process. But the most important stimulus causing overexpression of the B1 receptor was found to be the disruption of the B2 receptor, whether it was due to functional inactivation via a selective B2 receptor antagonist or to the deletion of the B2 receptor gene. In such cases, the B1 receptor can take over some of the vasodilatory functions of the B2 receptor, but not its metabolic (insulin-sensitizing) function. Patients with end stage cardiac failure have increased cardiac B1 receptor
Chapter | 188 Bradykinin Peptides
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mRNA and protein levels, in contrast to B2 receptor mRNA and protein levels, which are significantly downregulated.22 It is unclear whether the upregulation of the B1 receptor in patients with heart failure contributes to tissue protection by enhancing regional blood flow, or has a detrimental effect by interacting with inflammatory mediators and further exacerbating the inflammatory process.22 Both ACE inhibitor and ARB therapies increase kinin peptide levels5,10 that may contribute to the therapeutic effects of these agents. Recently, the renin inhibitor aliskiren was shown to increase bradykinin levels in the heart and lung of the rat, associated with increases in tissue kallikrein mRNA and protein levels.11 Studies with tissue kallikrein gene knockout mice confirm the role of the KKS in mediating cardioprotection by ACE inhibitor and ARB therapies.28 The importance of the B2 receptor in mediating in part the benefits of ACE inhibitor and ARB therapies is illustrated by the effects of icatibant, which attenuates the hypotensive effects of ACE inhibition in humans,5 and also attenuates angiogenesis and reduction of cardiac hypertrophy, infarct size, and fibrosis produced by these therapies in animal models. The B2 receptor is also implicated in the improvement in ischemic preconditioning, and in insulin sensitivity, reported with ACE inhibition.19,22 By contrast, treatment with a selective B1 receptor antagonist in the setting of myocardial infarction did not modify myocardial infarct size, but reversed the cardioprotective effects of ARB therapy, an effect attributed to cross-talk between the AT1 and B1 receptors.22 Both the B1 and B2 receptors are implicated in the promotion of angiogenesis by ACE inhibition.19,31 The potential for the KKS to contribute to inflammation is well illustrated by the clinical condition of angioneurotic edema, whereby C1 esterase inhibitor deficiency results in unpredictable activation of the contact system, leading to angioedema and increased circulating bradykinin levels (Fig. 5).5 The role of kinins in angioneurotic edema is demonstrated by the therapeutic benefits of icatibant and plasma kallikrein inhibition.17 Local tissue trauma and sepsis produce local kallikrein activation, possibly involving the contact system, and kinins contribute to the cardinal features of inflammation, producing vasodilatation, increased blood flow, vascular permeability, edema, neutrophil chemotaxis, and pain.3 Increased kinin peptide levels may contribute to the increased incidence of angioedema associated with ACE inhibitor and ARB therapies.5,10 Kinin levels are increased further when neutral endopeptidase 24.11 (NEP) inhibition is combined with ACE inhibition. Consequently, the incidence of angioedema is higher with combined ACE and NEP inhibition than with ACE inhibition alone.7 Moreover, reduced plasma levels of aminopeptidase P are associated with ACE inhibitor-induced angioedema.1 Patients with heart failure have reduced circulating levels of bradykinin
and kallidin peptides5 that may account for the lower incidence of angioedema in subjects with heart failure treated with ACE inhibitors or vasopeptidase inhibitors.7 In summary, kinin peptides exert a broad range of cardioprotective and inflammatory actions. In general, low physiological levels of kinin peptides play an important role in cardiovascular homeostasis, particularly in relation to sodium homeostasis and in cardioprotection, whereas the high pathological levels of kinin peptides that occur when the contact system is activated and may also occur when key kininase enzymes such as ACE, NEP and aminopeptidase P are inhibited, contribute to inflammation.
ACKNOWLEDGMENTS Duncan Campbell (Grant ID 395508) is a recipient of a Senior Research Fellowship from the National Health and Medical Research Council of Australia. This work was supported partly by the Victorian Government’s Operational Infrastructure Support Program.
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