アンジオテンシンⅡ刺激による血管平滑筋細胞の遊走に対するSrc阻害とMAPキナーゼ阻害効果の比較

Abstract

Angiotensin Ⅱ (AⅡ) plays an important role in various cardiovascular diseases associated with vascular smooth muscle cell (VSMC) growth and migration. In our previous study, we investigated the effect of olmesartan, an angiotensin Ⅱ receptor blocker, on AⅡ-induced Src tyrosine kinase, extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation and rat aortic smooth muscle cell (RASMC) migration. We found that olmesartan inhibited AⅡ-induced ERK1/2 and JNK activation at lower concentrations. On the other hand, PP2, a Src tyrosine kinase inhibitor, also inhibited AⅡ-induced ERK1/2 and JNK activation, but its effect on ERK1/2 was less pronounced than that of olmesartan. However, both olmesartan and PP2 potently inhibited AⅡ-induced RASMC migration. In the present study, we investigated the involvement of Src on AⅡ-induced migration of RASMC using Src siRNA for gene silencing. Src siRNA was successfully introduced into RASMC using transfection procedures. We found that the inhibitory effect of Src siRNA on AⅡ-induced JNK activation was more potent than on ERK1/2 activation in RASMC. In addition, Src siRNA effectively inhibited AⅡ-induced RASMC migration to an extent similar to PP2. From these findings, it was inferred that direct inhibition of Src may be an effective option for VSMC growth and migration. Pharmacological or genetic inhibition of Src may be a strategy that can be used in addition to renin-angiotensin blockade for cardiovascular diseases involving AⅡ, such as hypertension and atherosclerosis.