Mas-Mediated Antioxidant Effects Restore the Functionality of Angiotensin Converting Enzyme 2-Angiotensin-(1–7)-MasAxis in Diabetic Rat Carotid
We hypothesized that endothelial AT1-activated NAD(P)H oxidase-driven generation of reactive oxygen species during type I-diabetes impairs carotid ACE2-angiotensin-(1–7)-Masaxis functionality, which accounts for the impaired carotid flow in diabetic rats. We also hypothesized that angiotensin-(1–7) chronic treatment of diabetic rats restores carotid ACE2-angiotensin-(1–7)-Masaxis functionality and carotid flow. Relaxant curves for angiotensin II or angiotensin-(1–7) were obtained in carotid from streptozotocin-induced diabetic rats. Superoxide or hydrogen peroxide levels were measured by flow cytometry in carotid endothelial cells. Carotid flow was also determined. We found that endothelial AT1-activated NAD(P)H oxidase-driven generation of superoxide and hydrogen peroxide in diabetic rat carotid impairs ACE2-angiotensin-(1–7)-Masaxis functionality, which reduces carotid flow. In this mechanism, hydrogen peroxide derived from superoxide dismutation inhibits ACE2 activity in generating angiotensin-(1–7) seemingly by activatingICl,SWELL, while superoxide inhibits the nitrergicMas-mediated vasorelaxation evoked by angiotensin-(1–7). Angiotensin-(1–7) treatment of diabetic rats restored carotid ACE2-angiotensin-(1–7)-Masaxis functionality by triggering a positive feedback played by endothelialMasreceptors, that blunts endothelial AT1-activated NAD(P)H oxidase-driven generation of reactive oxygen species.Mas-mediated antioxidant effects also restored diabetic rat carotid flow, pointing to the contribution of ACE2-angiotensin-(1–7)-Masaxis in maintaining carotid flow.