부산대학교 도서관

Objective: Vascular smooth muscle cell (VSMC) proliferation and remodeling of the extracellular matrix contribute to lumen loss after arterial injury leading to restenosis. Matrix metalloproteinases (MMP) play an important role in this process by degrading structural proteins and enabling VSMCs to migrate. We previously showed that upregulation of cGMP-signaling prevents neointimal hyperplasia. In the present study, we investigated the effects of cinaciguat, a soluble guanylate cyclase (sGC)-activator on gene regulation during neointima formation.Methods and Results: Eighty male Sprague-Dawley rats underwent endothelial denudation by wire-injury of the right common carotid artery. Cinaciguat (10mg/kg/day orally) were administered to 40 rats (1-, 2-, 3-day and 1-, 2-, 3-week treatment time), while 40 rats received placebo. Left carotids served as sham controls. Cinaciguat-treatment significantly reduced neointima/media area ratio (0.45 ± 0.32 in the treatment group vs. 1.09 ± 0.69 in the control wire-injury group) and percent stenosis (17.53 ± 10.84% in the treatment group vs. 43.25 ± 30.83% in the control wire-injury group) 3 weeks after endothelial denudation, as assesed by haematoxylin-eosin stained cross-sections. By using quantitative real-time PCR, MMP-9 was significantly upregulated in the control-injured carotids at each of the six time intervals, whereas proliferating cell nuclear antigene (PCNA) gene expression increased mainly within the first week. Cinaciguat significantly reduced PCNA expression from the third day post-injury, whereas MMP-9 expression was downregulated during the whole follow-up. Plasma cGMP-concentration –as assessed by competitive enzyme immunoassay- did not change in the first three post-injury days in treated animals, and were elevated at 1- and 2-week follow-up, however the difference was not significant.Conclusion: Our results show that pharmacologic activation of sGC prevents injury-induced neointimal hyperplasia by regulating proliferation and MMP-9 expression.