Experimental Laboratory of Cardiac Surgery, University of Heidelberg, Germany.
Int J Cardiol. 2013 Jul 31;167(2):470-7. doi: 10.1016/j.ijcard.2012.01.032. Epub 2012 Feb 20.
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.
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.
Our results show that cinaciguat prevents injury-induced neointimal hyperplasia by decreasing VSMC migration and proliferation through the regulation of MMP-9.
血管平滑肌细胞（VSMC）的迁移、增殖和细胞外基质的重塑导致动脉损伤后管腔丢失，进而导致再狭窄。几项研究表明环鸟苷酸信号在新生内膜形成中的作用。西那卡塞，新型可溶性鸟苷酸环化酶激活剂，目前正在进行 IIb 期临床试验，已被证明在血管病理学动物模型中具有抗血小板和抗重塑作用。在这项研究中，我们研究了西那卡塞对损伤后动脉狭窄的影响。
雄性 Sprague-Dawley 大鼠（n=100）通过右颈总动脉的钢丝损伤使内皮细胞剥脱。西那卡塞（每天 10mg/kg 口服）给予 50 只大鼠（1、2、3 天和 1、3 周治疗时间），而 50 只大鼠给予安慰剂。3 周的治疗导致血管狭窄明显减少（治疗组 17.53 ± 10.84%，对照组钢丝损伤组 43.25 ± 30.83%）和新生内膜/中膜面积比（治疗组 0.45 ± 0.32，对照组钢丝损伤组 1.09 ± 0.69）。通过实时定量 PCR、Western blot 和免疫组织化学，基质金属蛋白酶-9（MMP-9）在整个随访过程中在对照组损伤的颈动脉中上调，西那卡塞在 3 周时显著降低 MMP-9 的表达。通过蛋白质免疫印迹评估，西那卡塞可恢复损伤诱导的可溶性鸟苷酸环化酶β1 亚基的局部减少。体外血管平滑肌细胞划痕愈合试验显示西那卡塞呈剂量依赖性的抗迁移和抗增殖作用。3 周治疗后，血浆中环鸟苷酸水平显著升高。
我们的结果表明，西那卡塞通过调节 MMP-9 降低 VSMC 的迁移和增殖来预防损伤诱导的新生内膜增生。
