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

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-...

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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
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Summary:	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.
ISSN:	1521-0103
DOI:	10.1124/jpet.110.175182