title: MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality.
abstract: AT1 antagonists effectively prevent atherosclerosis since AT1 upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT1 antagonists, the cross-talk between angiotensin-converting enzyme-angiotensin II-AT1 and angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axes suggests other mechanisms beyond AT1 blockage in such effects. For instance, angiotensin-converting enzyme 2 activity is inhibited by reactive oxygen species derived from AT1-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT1 antagonists could result from their inhibitory effects on the AT1-mediated negative modulation of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. Interestingly, our results showed that early atherosclerosis triggered in thoracic aorta from high cholesterol fed-Apolipoprotein E-deficient mice impairs angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality by a proinflammatory-redox AT1-mediated pathway. In such mechanism, AT1 activation leads to the aortic release of tumor necrosis factor-α, which stimulates NAD(P)H oxidase/Nox1-driven generation of superoxide and hydrogen peroxide. While hydrogen peroxide inhibits angiotensin-converting enzyme 2 activity, superoxide impairs MAS functionality. Candesartan treatment restored the functionality of angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis by inhibiting the proinflammatory-redox AT1-mediated mechanism. Candesartan also promoted vasoprotective and atheroprotective effects that were mediated by MAS since A779 (MAS antagonist) co-treatment inhibited them. The role of MAS receptors as the final mediators of the vasoprotective and atheroprotective effects of candesartan was supported by the vascular actions of angiotensin-(1-7) upon the recovery of the functionality of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences from Ribeirão Preto (FCFRP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil. Electronic address: l.pernomian@usp.br.
authors.forename: Larissa
authors.initials: L
authors.lastname: Pernomian
authors.affiliation: Department of Pharmacology, Faculty of Medicine from Ribeirão Preto (FMRP), USP, Ribeirão Preto, SP, Brazil.
authors.forename: Alejandro F
authors.initials: AF
authors.lastname: do Prado
authors.affiliation: Department of Physics and Chemistry, FCFRP, USP, Ribeirão Preto, SP, Brazil.
authors.forename: Mayara S
authors.initials: MS
authors.lastname: Gomes
authors.affiliation: Department of Pharmacology, Faculty of Medicine from Ribeirão Preto (FMRP), USP, Ribeirão Preto, SP, Brazil.
authors.forename: Laena
authors.initials: L
authors.lastname: Pernomian
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences from Ribeirão Preto (FCFRP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
authors.forename: Carlos H T P
authors.initials: CHTP
authors.lastname: da Silva
authors.affiliation: Department of Morphology, Faculty of Odontology from Ribeirão Preto (FORP), USP, Ribeirão Preto, SP, Brazil.
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Gerlach
authors.affiliation: Department of Physics and Chemistry, FCFRP, USP, Ribeirão Preto, SP, Brazil.
authors.forename: Ana M
authors.initials: AM
authors.lastname: de Oliveira
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002316:Cardiotonic Agents; D016207:Cytokines; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D013777:Tetrazoles; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1; D000803:Angiotensin I; D002784:Cholesterol; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); C081643:candesartan
keywords: AT(1) receptors; Angiotensin-(1-7); Angiotensin-converting-enzyme 2; Candesartan; Early atherosclerosis; MAS receptors