Aims: Angiotensin II participates to the regulation of cardiovascular physiology and it is involved in molecular mechanisms of insulin resistance. Angiotensin (1-7), derived from angiotensin II metabolism, is able to counteract many of the haemodynamic and non-haemodynamic actions of angiotensin II. In this study, we investigated in human umbilical vein endothelial cells (HUVECs) the possible action of angiotensin (1-7) on the insulin signalling pathway.
Methods and results: We stimulated HUVECs with insulin, angiotensin II and angiotensin (1-7), testing the effects on endothelial nitric oxide synthase (eNOS) enzyme activation and on insulin receptor substrate-1 (IRS1) phosphorylation. Moreover, we analysed the involvement of angiotensin type1, type2, and Mas receptors in these actions. Finally, we measured the nitric oxide (NO) production, the intracellular cGMP and the PKG-related activity in HUVECs, and the subsequent functional vasoactive effect of angiotensin (1-7) in mesenteric arteries of mice. Angiotensin II inhibits the insulin-induced Akt and eNOS phosphorylation, reducing the NO production. On the other hand, angiotensin (1-7) counteracts the inhibitory effect of angiotensin II, being able to restore the insulin-induced Akt/eNOS activation and the NO production. This effect is mediated by the Mas receptor. The inhibitory effects of angiotensin II on insulin signalling are, at least in part, mediated by an increased serine phosphorylation of IRS₁. Angiotensin (1-7) inhibits the serine phosphorylation of IRS1 induced by angiotensin II.
Conclusion: In endothelial cells angiotensin (1-7) counteracts the negative effects of angiotensin II on insulin signalling and NO production. The balance between angiotensin II and angiotensin (1-7) could represent a key mechanism in the pathophysiological processes leading to endothelial dysfunction and insulin-resistance.
Keywords: Angiotensin (1–7); Endothelium; Insulin; Nitric oxide.