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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 336; no. 3; p. 643
• Main Authors: Chieng-Yane, Pauline, Bocquet, Arnaud, Létienne, Robert, Bourbon, Thierry, Sablayrolles, Sylvie, Perez, Michel, Hatem, Stéphane Nicolas, Lompré, Anne-Marie, Le Grand, Bruno, David-Dufilho, Monique
• Format: Journal Article
• Language: English
• Published: United States 01-03-2011
• Subjects: Animals; Carotid Stenosis - metabolism; Carotid Stenosis - prevention & control; Cell Movement - drug effects; Cell Movement - physiology; Cell Proliferation - drug effects; Cells, Cultured; Coronary Restenosis - drug therapy; Coronary Restenosis - metabolism; Down-Regulation - drug effects; Down-Regulation - physiology; Gene Expression Regulation, Enzymologic; Humans; Male; Matrix Metalloproteinase 7 - biosynthesis; Matrix Metalloproteinase Inhibitors; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - metabolism; Piperazines - pharmacology; Piperazines - therapeutic use; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Rats, Sprague-Dawley; Receptor, PAR-1 - antagonists & inhibitors; Receptor, PAR-1 - physiology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1521-0103
• DOI: 10.1124/jpet.110.175182

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.