Lehmann K, Powell J S
University of California at Davis Cancer Center, Sacramento 95817.
J Cardiovasc Pharmacol. 1993;22 Suppl 4:S19-24. doi: 10.1097/00005344-199322004-00004.
Cilazapril, a novel long-acting inhibitor of angiotensin-converting enzyme, markedly suppressed the proliferative response and neointima formation after balloon catheter-induced injury of the carotid artery in a rat model of angioplasty. The reduction in neointima was dose-dependent, required sustained high levels of enzyme inhibition, and was significantly greater in animals treated starting 6 days prior to the procedure than in animals starting treatment the day of catheterization. In experiments with vascular smooth-muscle cells (SMC) in culture, the addition of angiotensin II reduces increased mRNA levels for several growth factors and extracellular matrix proteins. Here we report that Ang II selectively induces mRNA for thrombospondin I, but not for thrombospondin II. Under selected conditions SMC can be induced to proliferate after exposure to Ang II, in vitro and in vivo. Using neutralizing anti transforming growth factor beta (TGF-beta) antibodies we found that Ang II stimulation of proliferation was threefold greater when the anti-TGF-beta was added to the cultures. We suggest (a) that an important effect of Ang II during the proliferative response is the induction of thrombospondin I, which is required for matrix interactions during the formation of neointima, and (b) that, among the complex array of growth factors potentially active in vivo, TGF-beta may be an important negative regulatory factor that limits the proliferative response and prevents restenosis in most cases of angioplasty.
西拉普利是一种新型长效血管紧张素转换酶抑制剂，在大鼠血管成形术模型中，它能显著抑制球囊导管诱导的颈动脉损伤后的增殖反应和新生内膜形成。新生内膜的减少呈剂量依赖性，需要持续高水平的酶抑制作用，并且在手术前6天开始治疗的动物中比在导管插入术当天开始治疗的动物中显著更大。在体外培养血管平滑肌细胞（SMC）的实验中，添加血管紧张素II会降低几种生长因子和细胞外基质蛋白的mRNA水平升高。在此我们报告，血管紧张素II选择性地诱导血小板反应蛋白I的mRNA表达，但不诱导血小板反应蛋白II的mRNA表达。在特定条件下，SMC在体内外暴露于血管紧张素II后可被诱导增殖。使用中和抗转化生长因子β（TGF-β）抗体，我们发现当将抗TGF-β添加到培养物中时，血管紧张素II对增殖的刺激作用增加了三倍。我们认为：（a）血管紧张素II在增殖反应中的一个重要作用是诱导血小板反应蛋白I，这是新生内膜形成过程中基质相互作用所必需的；（b）在体内可能具有活性的一系列复杂生长因子中，TGF-β可能是一个重要的负调节因子，它在大多数血管成形术病例中限制增殖反应并防止再狭窄。
