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(Circulation. 2006;114:1070-1077.)
© 2006 American Heart Association, Inc.

Basic Science for Clinicians

Protease-Activated Receptors in Cardiovascular Diseases

Andrew J. Leger, BA; Lidija Covic, PhD; Athan Kuliopulos, MD, PhD

From the Hemostasis and Thrombosis Laboratory, Division of Hematology/Oncology, Molecular Oncology Research Institute, Tufts–New England Medical Center (A.J.L, L.C., A.K.), and Department of Biochemistry (A.J.L., A.K.), Tufts University School of Medicine, Boston, Mass.

Correspondence to Athan Kuliopulos, MD, PhD, Tufts–New England Medical Center, 750 Washington St, Box 7510, Boston, MA 02111. E-mail athan.kuliopulos{at}tufts.edu

Thrombosis associated with the pathophysiological activation of platelets and vascular cells has brought thrombin and its receptors to the forefront of cardiovascular medicine. Thrombin signaling through the protease-activated receptors (PARs) has been shown to influence a wide range of physiological responses including platelet activation, intimal hyperplasia, inflammation, and maintenance of vascular tone and barrier function. The thrombin receptors PAR1 and PAR4 can be effectively targeted in animals in which acute or prolonged exposure to thrombin leads to thrombosis and/or restenosis. In the present study, we describe the molecular and pharmacological basis of small-molecule inhibitors that target PAR1. In addition, we discuss a new class of cell-penetrating inhibitors, termed pepducins, that provide insight into previously unidentified roles of PAR1 and PAR4 in protease signaling.

Key Words: arteries • endothelium • inhibitors • platelets • receptors • signal transduction • thrombosis

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