Cinaciguat prevents neointima formation after arterial injury by the regulation of genes responsible for extracellular matrix metabolism

Remodeling of the extracellular matrix contribute to lumen loss after arterial injury. Matrix metalloproteinases (MMP) play an important role in this process by degrading structural proteins of the vascular wall and enabling medial smooth muscle cells to migrate and proliferate. 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 neointima formation. Twentytwo Sprague-Dawley rats underwent endothelial denudation by wire-injury of the right common carotid artery. Cinaciguat (10mg/kg/day, intraperitoneally) were administered to 10 rats, while 12 rats received placebo. Left carotids served as sham controls. Vessel areas were compared after 21 days by using haematoxylin-eosin stained cross-sections. TUNEL (terminal deoxynucleotidyl transferase dUTP-nick end-labelling) assay was performed to assess DNA strandbreaks in the vascular wall. Quantitative real-time PCR were performed to evaluate relative gene expression of collagen-1, -3, MMP-2, -9, cyclooxygenase-2 (COX-2), iNOS and eNOS in the carotids; ß-actin served as reference gene. Cinaciguat-treatment significantly reduced neointima/media area ratio (0.454±0.315 vs. 1.086±0.691 in the control-injured carotids) and percent stenosis (17.530±10.845% vs. 43.250±30.833%) after wire-injury. TUNEL-positivity decreased both in the media (23.228±10.809% vs. 32.581±15.810%) and neointima (35.202±12.367% vs. 43.454±17.368%) in the treatment group. MMP-9 in the control-injured carotids were significantly upregulated, accompanied by decrease in collagen-1 and -3 mRNA-expression, while COX-2, iNOS and eNOS remained unchanged. Cinaciguat significantly reduced MMP-9 and COX-2 mRNA-level and increased collagen-1, -3 and eNOS expression. Our results show, that pharmacologic activation of sGC prevent injury-induced neointimal hyperplasia by regulating MMP-9 and collagenes.