Affiliation:
1. the Hematology and Oncology Division, Department of Internal Medicine, University of Michigan (Ann Arbor).
Abstract
Background
Plasma kininogens are selective inhibitors of α-thrombin activation of platelets and endothelial cells. In the present study, we localized the α-thrombin inhibitory sequence of kininogens and describe its mechanism of action.
Methods and Results
Bradykinin and an analogue, MKRPPGFSPFRSSRIG, inhibited α-thrombin–induced platelet aggregation and secretion with an IC
50
of 0.25 and 1 mmol/L and of 0.23 and 0.5 mmol/L, respectively. The minimal inhibitory peptide was RPPGF. Bradykinin and its analogues did not inhibit ADP-, collagen-, U46619-, or SFLLRN-induced platelet activation or the ability of α-thrombin to cleave chromogenic substrates, clot fibrinogen, or block α-thrombin binding to platelets. Bradykinin, MKRPPGFSPFRSSRIG, and RPPGF abolished α-thrombin–induced (1 nmol/L) calcium mobilization. On flow cytometry, bradykinin and MKRPPGFSPFRSSRIG blocked α-thrombin from removing the epitope of its cleavage site on the cloned thrombin receptor. Furthermore, peptide RPPGF or high-molecular-weight kininogen prevented α-thrombin from cleaving the thrombin receptor peptide, NATLDPRSFLLR, between arginine and serine.
Conclusions
These results indicate that bradykinin and its metabolites are selective antithrombins by preventing α-thrombin cleavage of the cloned thrombin receptor between arginine-41 and serine-42. These newly recognized antithrombin peptides, which are termed thrombostatins, contribute to the cardioprotective nature of kinins.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
91 articles.
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