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Blood, 1 July 2006, Vol. 108, No. 1, pp. 1-2.
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HEMOSTASIS
Comment on Shariat-Madar et al, page 192
Is the plasma kallikrein-kinin system antithrombotic?
Robert W. Colman
TEMPLE UNIVERSITY SCHOOL OF MEDICINE
In this issue, Shariat-Madar and colleagues provide evidence that BK B2 receptor knockout (BKB2R-/-) mice have a long bleeding time and delayed thrombosis that depends in part on nitric oxide and prostacyclin elevation produced by angiotensin II binding to an overexpressed receptor.
In vitro, there was a markedly decreased concentration of a component of the plasma kallikrein-kinin system (KKS) that appeared to result in defective coagulation, which was shown by the prolonged aPTT in patients and experimental animals with low plasma levels of factor XII, prekallikrein, or high-molecular-weight kininogen (HK). However, hereditary deficiency of any of these proteins is not associated with excessive or spontaneous bleeding. Plasma kallikrein is a kinetically favorable activator of prourokinase to urokinase.1 Urokinase binds to its receptor, uPAR, on the endothelial-cell surface. Since prekallikrein binds to HK, which associates with the same receptor, the conversion of plasminogen to plasmin is efficient and probably represents the in vivo site.2 Thus, prekallikrein may be an antithrombotic protein by virtue of its role in the fibrinolytic system. The substrate of the KKS HK also displays antithrombotic activity. HK inhibits thrombin-induced platelet activation,3 and an HK-deficient rat exhibits much more rapid onset of arterial thrombosis following endothelial injury.4 Two distinct sequences from domain 3 and domain 4 are each capable of inhibiting thrombin-induced platelet activation, although the affinities and the mechanism are different. Most of the inhibitory activity of domain 3 is in the region coded for by exon of G235-Q292 (IC50 = 0.2 µM).5 This sequence competes with thrombin for binding to platelet GPIb. The second sequence in domain 4 is minimally contained in the breakdown product of bradykinin, catalyzed by ACE, bradykinin 1-5 peptide RPPGF.6 In the current article, Shariat-Madar and colleagues demonstrated that mice lacking the constitutive BKB2R exhibit decreased risk for thrombosis. The animals have delayed thrombosis in an endothelial-cell photochemical injury model due to local free radical release as well as a prolonged bleeding time compared with mice with normal levels of BKB2R in the same genetic background. The authors then analyzed the mechanisms of thromboprotection (see figure).
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The top diagram indicates the kallikrein-kinin system (KKS) interaction in the normal mouse and shows its interaction and balance with the angiotensin system. The lower diagram shows the changes occurring when the bradykinin receptor 2 (BKB2R) is "knocked out." The size of the blocks indicates the amount of protein present in the normal and knockout mouse. The shape of the symbol represents its function. Blocks with pointed edges are proteolytic enzymes. Spheres and ellipsoids are substrates of proteases. Jagged edges denote proteolytic degradation products. Cups with stems crossing cell membranes are receptors. HK indicates high-molecular-weight kininogen; PRCP, prolylcarboxpeptidase; AT1R, angiotensin 1 receptor; AT2R, angiotensin 2 receptor; and X, gene knockout. Illustration by A. Y. Chen.
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The BKB2R-/- mice had elevated prekallikrein, which produced an increased bradykinin level, but bradykinin is very rapidly hydrolyzed by ACE and so cannot be directly measured. The investigators indirectly showed that BK was increased by finding that the knockout mice had high levels of both of the enzymatic products of ACE: BK 1-5 and angiotensin II. In order to ascertain whether the elevated angiotensin II was related to the delayed thrombosis, the authors treated the BKB2R-/- mice with the ACE inhibitor ramipril and demonstrated a significant shortening of the time to thrombosis. They then addressed the mechanism by which angiotensin II elevation could lengthen bleeding times and delay stimulated vessel closure. They found both NO (measured as nitrate) and prostacyclin (measured as  -keto-prostaglandin F1 ) were elevated in the knockout mice. These elevated levels in the BKBB2R-/- could be reversed by either a nitric oxide synthetase inhibitor or a cyclooxygenase-2 inhibitor. BKB2R-/- mice have increased angiotensin receptor 2 (AT2R) as measured by mRNA and protein. An AT2R receptor antagonist normalizes both the time to thrombosis and the nitrate and 6-keto-PGF1. Thus, the mechanism for thromboprotection is angiotensin binding to an overexpressed AT2R, which elevates nitric oxide and prostacyclin. This elegant study demonstrates that plasma angiotensin II elevation could result from increased ACE activity due to the need to metabolize more bradykinin as a result of an indirect effect of the lack of BKB2R. This conclusion reinforces recent evidence that angiotensin II receptors and bradykinin receptors may interact and regulate each other at the level of the receptor.7 
References
- Ichinose A, Fujikawa K, Suyama T. The activation of pro-urokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem. 1986;261: 3486-3489.[Abstract/Free Full Text]
- Lin Y, Harris RB, Yan WY, McCrae KR, Colman RW. Inhibition of prourokinase-activated fibrinolysis on endothelial cell surfaces by high molecular weight kininogen peptides. Blood. 1997;90: 690-697.[Abstract/Free Full Text]
- Puri RN, Colman RW. Inhibition of ADP-induced platelet shape change and aggregation by o-phthalaldehyde: evidence for covalent modification of cysteine and lysine residues. Arch Biochem Biophys. 1991;286: 419-427.[CrossRef][Medline]
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- Colman RW, White JV, Scovell S, Stadnicki A, Sartor RB. Kininogens are antithrombotic proteins in vivo. Arterioscler Thromb Vasc Biol. 1999;19: 2245-2250.[Abstract/Free Full Text]
- Kunapuli SP, Bradford HN, Jameson BA, et al. Thrombin-induced platelet aggregation is inhibited by the heptapeptide Leu271-Ala277 of domain 3 in the heavy chain of high molecular weight kininogen. J Biol Chem. 1996;271: 11228-11235.[Abstract/Free Full Text]
- Hasan AA, Amenta S, Schmaier AH. Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitor of alpha-thrombin-induced platelet activation. Circulation. 1996;94: 517-528.[Abstract/Free Full Text]
- Tan Y, Hutchison FN, Jaffa AA. Mechanisms of angiotensin II-induced expression of B2 kinin receptors. Am J Physiol Heart Circ Physiol. 2004;286: H926-H932.[Abstract/Free Full Text]
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