title: Cinaciguat prevents neointima formation after arterial injury by decreasing vascular smooth muscle cell migration and proliferation.
abstract: OBJECTIVE
  Vascular smooth muscle cell (VSMC) migration, proliferation and remodeling of the extracellular matrix contribute to lumen loss after arterial injury leading to restenosis. Several studies indicated the role of the cyclic guanosine monophosphate signaling in neointimal formation. Cinaciguat, the novel soluble guanylate cyclase activator, currently being in phase IIb clinical trial, has been shown to exert antiplatelet and anti-remodeling effects in animal models of vascular pathology. In this study we investigated the effects of cinaciguat on post-injury arterial stenosis.
  
  
  RESULTS
  Male Sprague-Dawley rats (n=100) underwent endothelial denudation by wire injury of the right common carotid artery. Cinaciguat (10mg/kg/day orally) were administered to 50 rats (1-, 2-, 3-day and 1-, 3-week treatment time), while 50 rats received placebo. A 3-week treatment resulted in a significantly reduced vascular stenosis (17.53 ± 10.84% in the treatment group vs. 43.25 ± 30.83% in the control wire injury group) and neointima/media area ratio (0.45 ± 0.32 in the treatment group vs. 1.09 ± 0.69 in the control wire injury group). By using quantitative real-time PCR, Western blot and immunohistochemistry, matrix-metallopreoteinase-9 (MMP-9) was found to be upregulated in the control-injured carotids over the whole follow-up, and cinaciguat significantly decreased MMP-9 expression by 3 weeks. As assessed by protein immunoblot, injury-induced local decrease of soluble guanylate cyclase β1 subunit could be recovered by cinaciguat. In vitro wound healing assay with VSMCs revealed dose-dependent antimigratory and antiproliferative effects of cinaciguat. Plasma level of cyclic guanosine monophosphate was significantly elevated after 3 weeks of treatment.
  
  
  CONCLUSIONS
  Our results show that cinaciguat prevents injury-induced neointimal hyperplasia by decreasing VSMC migration and proliferation through the regulation of MMP-9.
authors.affiliation: Experimental Laboratory of Cardiac Surgery, University of Heidelberg, Germany. hirschbergkristof@gmail.com
authors.forename: K
authors.initials: K
authors.lastname: Hirschberg
authors.forename: V
authors.initials: V
authors.lastname: Tarcea
authors.forename: Sz
authors.initials: S
authors.lastname: Páli
authors.forename: E
authors.initials: E
authors.lastname: Barnucz
authors.forename: P N
authors.initials: PN
authors.lastname: Gwanmesia
authors.forename: S
authors.initials: S
authors.lastname: Korkmaz
authors.forename: T
authors.initials: T
authors.lastname: Radovits
authors.forename: S
authors.initials: S
authors.lastname: Loganathan
authors.forename: B
authors.initials: B
authors.lastname: Merkely
authors.forename: M
authors.initials: M
authors.lastname: Karck
authors.forename: G
authors.initials: G
authors.lastname: Szabó
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058426:Neointima / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001565:Benzoates; C480588:BAY 58-2667; D020780:Matrix Metalloproteinase 9; D006162:Guanylate Cyclase