Inhibitory effects of trapidil on PDGF signaling in balloon-injured rat carotid artery.
Trapidil, which was originally developed as an anti-platelet agent, is among the few agents thus far proven to be clinically effective in preventing restenosis after percutaneous coronary interventions. Trapidil was previously shown to inhibit platelet-derived growth factor (PDGF)-induced cellular responses in vitro in cultured cells. However, its mechanism of action is poorly understood. In this study, we investigated by using a rat carotid balloon-injury model whether and how trapidil inhibited the in vivo action of PDGF, which is regarded as a most important growth factor implicated in proliferation and migration of vascular smooth muscle cells. The combination of both oral and topical administration of trapidil reduced the intimal lesion size by more than 70% and nearly completely suppressed injury-induced increases in phosphotyrosine content of PDGF alpha- and beta- receptors of carotid artery. Moreover, trapidil was found to decrease mRNA levels of PDGF alpha- and beta- receptors strongly and of PDGF A- and B- chains moderately in injured arteries. These results indicate that trapidil potently suppresses the action of PDGF with inhibition of neointima formation in injured artery, which is mediated at least in part through decreasing the expression of both PDGF ligands and their receptors.
Deguchi
J
J
Department of Molecular and Cellular Physiology, University of Tokyo School of Medicine, Japan.
Abe
J
J
Makuuchi
M
M
Takuwa
Y
Y
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008024:Ligands; D008297:Male; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014192:Trapidil / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D008024:Ligands; D010982:Platelet-Derived Growth Factor; D014665:Vasodilator Agents; D014443:Tyrosine; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D014192:Trapidil