Abstract 14339: F 16618, A New Par1 Antagonist Prevents Restenosis by Inhibiting Migration and Proliferation of Smooth Muscle Cells.
Objectives: Wound healing responses after angioplasty or stenting are associated with increased production of thrombin and activation of protease activated receptor 1 (PAR1). The aim of the present study was to evaluate the putative role of F 16618, a new selective PAR1 antagonist on vascular smooth muscle cell proliferation and restenosis using both in vitro and in vivo approaches.
Methods and Results: Daily oral administration of F 16618 dose-dependently inhibited the restenosis induced by balloon angioplasty on rat carotid artery. A unique i.v. treatment with F 16618 during the surgical angioplasty procedure had similar effect, showing that early inhibition of PAR1 was highly efficient to protect carotid against restenosis. In human aortic smooth muscle cells, F 16618 dose-dependently inhibited serum-induced cell growth with a maximal effect at 100μM. However, a dose of 10μM was sufficient to suppress cell proliferation induced by PAR1 agonists SFLLR and thrombin. A this concentration, F 16618 also prevented migration of human aortic smooth muscle cells in response to thrombin. In the in vivo model, oral and i.v. F 16618 treatments did not avoid early induction of MCP-1 transcription, and decrease in contractile protein smoothelin and endothelial marker thrombomodulin observed 24 h after the balloon angioplasty. Labeling of injured carotid sections with fluorescent antibody to von Willebrand factor showed that reendothelialization had started 14 days after the surgery. F 16618 treatments had no effect on this early reendothelialization process. In addition, F 16618 compensated the endothelium loss of rat carotid artery by inhibiting contraction mediated by PAR1 agonists SFLLR and thrombin.
Conclusions: Altogether, these data demonstrate that PAR1 antagonists such as F 16618 could be highly effective treatment of restenosis attendant to vascular injury by preventing proliferation and migration of smooth muscle cells in addition to their anti-thrombotic effect.
- © 2010 by American Heart Association, Inc.