title: MAS-mediated antioxidant effects restore the functionality of angiotensin converting enzyme 2-angiotensin-(1-7)-MAS axis in diabetic rat carotid.
abstract: 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 I(Cl,SWELL0, 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.
authors.affiliation: Faculdade de Ciencias Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Larissa
authors.identifier: 0000-0002-1201-7753
authors.initials: L
authors.lastname: Pernomian
authors.affiliation: Faculdade de Ciencias Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Mayara Santos
authors.initials: MS
authors.lastname: Gomes
authors.affiliation: Faculdade de Medicina, Universidade de Ribeirão Preto, Avenida Costábile Romano 2201, 14096-900 Ribeirão Preto, SP, Brazil.
authors.forename: Carolina Baraldi Araujo
authors.initials: CB
authors.lastname: Restini
authors.affiliation: Faculdade de Ciencias Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Ana Maria
authors.identifier: 0000-0002-2363-5434
authors.initials: AM
authors.lastname: de Oliveira
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001783:Blood Flow Velocity; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)