Wei Yongzhong, Whaley-Connell Adam T, Chen Kemin, Habibi Javad, Uptergrove Grace M-E, Clark Suzanne E, Stump Craig S, Ferrario Carlos M, Sowers James R
University of Missouri-Columbia, Harry S. Truman VA Medical Center, Columbia, MO, USA.
Hypertension. 2007 Aug;50(2):384-91. doi: 10.1161/HYPERTENSIONAHA.107.089284. Epub 2007 May 28.
Reduced insulin sensitivity is characteristic of various pathological conditions such as type 2 diabetes mellitus and hypertension. Angiotensin II, acting through its angiotensin type 1 receptor, inhibits the actions of insulin in the vasculature which may lead to deleterious effects such as vascular inflammation, remodeling, endothelial dysfunction, and insulin resistance. In contrast, insulin normally exerts vasodilatory, antiinflammatory, and prosurvival actions. To explore the impact of angiotensin II on insulin signaling, NADPH oxidase-derived reactive oxygen species formation, vascular inflammation, apoptosis, and remodeling, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and exhibits elevated tissue angiotensin II levels. Compared with Sprague-Dawley controls, Ren2 aortas exhibited greater NADPH oxidase activity, reactive oxygen species levels, C-reactive protein, tumor necrosis factor-alpha expression, apoptosis, and wall thickness, which were significantly attenuated by in vivo treatment with angiotensin type 1 receptor blockade (valsartan) or the superoxide dismutase/catalase mimetic (tempol). There was substantially diminished Akt and endothelial NO synthase activation in Ren2 aortas in response to in vivo insulin stimulation, and this was significantly improved by in vivo treatment with valsartan or tempol. In vivo treatment with valsartan, but not tempol, significantly reduced blood pressure in Ren2 rats. Further, there was reduced insulin induced Akt activation and increased tumor necrosis factor-alpha levels in vascular smooth muscle cells from Ren2 and Sprague-Dawley rats treated with angiotensin II, abnormalities that were abrogated by angiotensin type 1 receptor blockade with valsartan or antioxidant N-acetylcysteine. Collectively, these data suggest that increased angiotensin type 1 receptor/NADPH oxidase activation/reactive oxygen species contribute to vascular insulin resistance, endothelial dysfunction, apoptosis, and inflammation.
胰岛素敏感性降低是2型糖尿病和高血压等多种病理状况的特征。血管紧张素II通过其1型血管紧张素受体发挥作用，抑制胰岛素在血管系统中的作用，这可能导致血管炎症、重塑、内皮功能障碍和胰岛素抵抗等有害影响。相比之下，胰岛素通常具有血管舒张、抗炎和促生存作用。为了探究血管紧张素II对胰岛素信号传导、NADPH氧化酶衍生的活性氧生成、血管炎症、细胞凋亡和重塑的影响，我们使用了转基因TG(mRen2)27（Ren2）大鼠，其携带小鼠肾素转基因且组织血管紧张素II水平升高。与Sprague-Dawley对照相比，Ren2大鼠的主动脉表现出更高的NADPH氧化酶活性、活性氧水平、C反应蛋白、肿瘤坏死因子-α表达、细胞凋亡和壁厚，而通过1型血管紧张素受体阻断剂（缬沙坦）或超氧化物歧化酶/过氧化氢酶模拟物（替莫泊芬）的体内治疗可显著减轻这些情况。在体内胰岛素刺激下，Ren2大鼠主动脉中Akt和内皮型一氧化氮合酶的激活明显减弱，而通过缬沙坦或替莫泊芬的体内治疗可显著改善这一情况。缬沙坦而非替莫泊芬的体内治疗可显著降低Ren2大鼠的血压。此外，在用血管紧张素II处理的Ren2和Sprague-Dawley大鼠的血管平滑肌细胞中，胰岛素诱导的Akt激活减少，肿瘤坏死因子-α水平升高，而用缬沙坦或抗氧化剂N-乙酰半胱氨酸进行1型血管紧张素受体阻断可消除这些异常情况。总体而言，这些数据表明，1型血管紧张素受体/ NADPH氧化酶激活/活性氧增加会导致血管胰岛素抵抗、内皮功能障碍、细胞凋亡和炎症。
