Protease-activated receptor-1 antagonist F 16618 reduces arterial restenosis by down-regulation of tumor necrosis factor α and matrix metalloproteinase 7 expression, migration, and proliferation of vascular smooth muscle cells.

Abstract

Wound healing after angioplasty or stenting is associated with increased production of thrombin and the activation of protease-activated receptor 1 (PAR1). The aim of the present study was to examine the effects of a new selective PAR1 antagonist, 2-[5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)-penta-1,3-dienyl]-benzonitrile (F 16618), in restenosis and vascular smooth muscle cell (SMC) proliferation and migration using both in vivo and in vitro approaches. Daily oral administration of F 16618 inhibited the restenosis induced by balloon angioplasty on rat carotid artery in a dose-dependent manner. Furthermore, single intravenous administration of F 16618 during the angioplasty procedure was sufficient to protect the carotid artery against restenosis. In vitro, F 16618 inhibited the growth of human aortic SMCs in a concentration-dependent manner with maximal effects at 10 μM. At that concentration, F 16618 also prevented thrombin-mediated SMC migration. In vivo, oral and intravenous F 16618 treatments reduced by 30 and 50% the expression of the inflammatory cytokine tumor necrosis factor α (TNFα) 24 h after angioplasty. However, only acute intravenous administration prevented the induction of matrix metalloproteinase 7 expression. In contrast, F 16618 treatments had no effect on early SMC de-differentiation and transcription of monocyte chemoattractant protein-1 and interleukin-6 and late re-endothelialization of injured arteries. Furthermore, F 16618 compensated for the carotid endothelium loss by inhibiting PAR1-mediated contraction. Altogether, these data demonstrate that PAR1 antagonists such as F 16618 are a highly effective treatment of restenosis after vascular injury, by inhibition of TNFα, matrix metalloproteinase 7, and SMC migration and proliferation in addition to an antithrombotic effect.

• Authors: Pauline Chieng-Yane, Arnaud Bocquet, Robert Létienne, Thierry Bourbon, Sylvie Sablayrolles, Michel Perez, Stéphane Nicolas Hatem, Anne-Marie Lompré, Bruno Le Grand, Monique David-Dufilho
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 336 Issue 3 Pg. 643-51 (Mar 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21139058 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3-dienyl)benzonitrile
• Matrix Metalloproteinase Inhibitors
• Piperazines
• Pyridines
• Receptor, PAR-1
• Tumor Necrosis Factor-alpha
• Matrix Metalloproteinase 7

Topics

• Animals
• Carotid Stenosis (metabolism, prevention & control)
• Cell Movement (drug effects, physiology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Coronary Restenosis (drug therapy, metabolism)
• Down-Regulation (drug effects, physiology)
• Gene Expression Regulation, Enzymologic
• Humans
• Male
• Matrix Metalloproteinase 7 (biosynthesis)
• Matrix Metalloproteinase Inhibitors
• Muscle, Smooth, Vascular (drug effects, enzymology, metabolism)
• Myocytes, Smooth Muscle (drug effects, enzymology, metabolism)
• Piperazines (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, PAR-1 (antagonists & inhibitors, physiology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)