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-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.
Institut de Recherche Pierre Fabre, Castres Cedex France.
Pauline
P
Chieng-Yane
Arnaud
A
Bocquet
Robert
R
Létienne
Thierry
T
Bourbon
Sylvie
S
Sablayrolles
Michel
M
Perez
Stéphane Nicolas
SN
Hatem
Anne-Marie
AM
Lompré
Bruno
B
Le Grand
Monique
M
David-Dufilho
D000818:Animals; D016893:Carotid Stenosis / Q000378:metabolism / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000188:drug therapy / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors
C542252:2-(5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3-dienyl)benzonitrile; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011725:Pyridines; D044463:Receptor, PAR-1; D014409:Tumor Necrosis Factor-alpha; D020783:Matrix Metalloproteinase 7; D010975:Platelet Aggregation Inhibitors