Inhibition of Neointima by Angiotensin-Converting Enzyme Inhibitor in Porcine Coronary Artery Balloon-Injury Model

Abstract

Because hepatocyte growth factor (HGF) stimulates growth of endothelial cells exclusively without replication of vascular smooth muscle cells, we hypothesized that HGF may play a role in cardiovascular disease. In human vascular smooth muscle cells, angiotensin II suppressed local vascular HGF production in a dose-dependent manner. Using a rat balloon-injury carotid artery model, we demonstrated that blockade of angiotensin II inhibited neointimal formation, accompanied by a significant increase in local HGF production. However, the relation of vascular HGF to endothelial function was not clarified. Moreover, it is important to test the hypothesis in animal models that are more similar to human restenosis. Thus, in the present study, we used a porcine coronary artery balloon-injury model to study the role of angiotensin II in regulation of the local HGF system in vivo. Expression of HGF mRNA was significantly decreased in balloon-injured coronary arteries versus intact vessels. An angiotensin-converting enzyme (ACE) inhibitor (perindopril) significantly inhibited neointimal formation after balloon injury compared with vehicle ( P <0.05). In addition, vasodilator response of balloon-injured coronary arteries to bradykinin was restored by perindopril treatment, whereas no vasodilator response was observed in balloon-injured vessels treated with vehicle. Vasodilator response of balloon-injured arteries induced by perindopril was completely abolished by N w -nitro- l -arginine methyl ester. Of particular interest, vascular HGF mRNA was significantly increased in balloon-injured vessels treated with perindopril as compared with vehicle. Overall, the present study demonstrated that ACE inhibitor significantly inhibited neointimal formation, accompanied by significant improvement of endothelial dysfunction and a significant increase in local vascular HGF mRNA in vivo in a porcine coronary artery balloon-injury model. Given the strong mitogenic activity of HGF on endothelial cells, improvement of endothelial dysfunction by perindopril might be due to increased local HGF expression through enhancement of reendothelialization after balloon injury, in addition to its direct effect, ACE inhibition. Downregulation of the local vascular HGF system may play an important role in the pathogenesis of cardiovascular disease.