Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093, USA.
Biochem Biophys Res Commun. 2012 Sep 28;426(3):369-73. doi: 10.1016/j.bbrc.2012.08.093. Epub 2012 Aug 28.
The nonapeptide angiotensin II (ANG II) induces vasoconstriction via the ANG II type I receptor, while its splice product ANG-(1-7) elicits an antihypertensive effect via the Mas receptor. Although a critical role of ANG II in the etiology of skeletal muscle insulin resistance is well documented, the role of the ANG-(1-7)/Mas receptor axis in this context is poorly understood. Therefore, we determined whether ANG-(1-7) is effective in ameliorating the negative effects of ANG II on insulin-stimulated insulin signaling and glucose transport activity in isolated soleus muscle from normotensive lean Zucker rats. ANG II alone (500 nM for 2 h) decreased insulin-stimulated glucose transport activity by 45% (P < 0.05). In the presence of 500-1000 nM ANG-(1-7), insulin-stimulated glucose transport activity in muscle exposed to ANG II improved by ~30% (P < 0.05). Moreover, ANG-(1-7) treatment increased Akt Ser(473) phosphorylation (47%, P < 0.05) without an effect on glycogen synthase kinase-3β Ser(9) phosphorylation. The dependence of ANG-(1-7) action on the Mas receptor was assessed using A779 peptide, a selective Mas receptor antagonist. The positive effects of ANG-(1-7) on insulin-stimulated glucose transport activity and Akt Ser(473) phosphorylation in soleus muscle were completely prevented in presence of 1000 nM A779. In conclusion, the present study demonstrates that ANG-(1-7), via a Mas receptor-dependent mechanism, can ameliorate the inhibitory effect of ANG II on glucose transport activity in mammalian skeletal muscle, associated with enhanced Akt phosphorylation. These results provide further evidence supporting the targeting of the renin-angiotensin system for interventions designed to reduce insulin resistance in skeletal muscle tissue.
血管紧张素 II（ANG II）通过 ANG II 型受体诱导血管收缩，而其剪接产物 ANG-(1-7) 通过 Mas 受体产生降压作用。虽然血管紧张素 II 在骨骼肌胰岛素抵抗的发病机制中起着至关重要的作用，但 ANG-(1-7)/Mas 受体轴在这种情况下的作用尚未得到很好的理解。因此，我们确定了 ANG-(1-7) 是否能有效改善血管紧张素 II 对正常血压瘦 Zucker 大鼠比目鱼肌胰岛素刺激的胰岛素信号和葡萄糖转运活性的负面影响。单独的 ANG II（2 小时 500 nM）使胰岛素刺激的葡萄糖转运活性降低了 45%（P < 0.05）。在 500-1000 nM ANG-(1-7) 的存在下，暴露于 ANG II 的肌肉中胰岛素刺激的葡萄糖转运活性提高了约 30%（P < 0.05）。此外，ANG-(1-7) 处理增加了 Akt Ser(473)磷酸化（47%，P < 0.05），而对糖原合酶激酶-3β Ser(9)磷酸化没有影响。通过使用 A779 肽（一种选择性 Mas 受体拮抗剂）评估了 ANG-(1-7) 作用对 Mas 受体的依赖性。在 1000 nM A779 存在的情况下，ANG-(1-7) 对比目鱼肌胰岛素刺激的葡萄糖转运活性和 Akt Ser(473)磷酸化的积极作用完全被阻止。综上所述，本研究表明，ANG-(1-7) 通过一种 Mas 受体依赖性机制，可以改善哺乳动物骨骼肌中 ANG II 对葡萄糖转运活性的抑制作用，同时增强 Akt 磷酸化。这些结果为针对骨骼肌组织胰岛素抵抗的干预措施靶向肾素-血管紧张素系统提供了进一步的证据。
