Mas-Mediated Antioxidant Effects Restore the Functionality of Angiotensin Converting Enzyme 2-Angiotensin-(1–7)‎-Mas Axis in Diabetic Rat Carotid

Abstract EN

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)-Mas axis 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)-Mas axis 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)-Mas axis functionality, which reduces carotid flow.

In this mechanism, hydrogen peroxide derived from superoxide dismutation inhibits ACE2 activity in generating angiotensin-(1–7) seemingly by activating ICl,SWELL, while superoxide inhibits the nitrergic Mas-mediated vasorelaxation evoked by angiotensin-(1–7).

Angiotensin-(1–7) treatment of diabetic rats restored carotid ACE2-angiotensin-(1–7)-Mas axis functionality by triggering a positive feedback played by endothelial Mas receptors, 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)-Mas axis in maintaining carotid flow.