MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality

Autor(es)

Pernomian, Larissa ^[1] ; do Prado, Alejandro F. ^[2] ; Gomes, Mayara S. ^[3] ; Pernomian, Laena ^[2] ; da Silva, Carlos H. T. P. ^[1] ; Gerlach, Raquel F. ^[4] ; de Oliveira, Ana M. ^[3]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto FCFRP, Dept Pharmaceut Sci, BR-14049 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pharmacol, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, FCFRP, Dept Chem & Phys, Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Fac Odontol Ribeirao Preto FORP, Dept Morphol, Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmacology; v. 764, p. 173-188, OCT 5 2015.
• Citações Web of Science: 11

Resumo

AT(1) antagonists effectively prevent atherosclerosis since AT(1) upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT(1) antagonists, the cross talk between angiotensin-converting enzyme-angiotensin II-AT(1) 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 AT(1)-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT(1) antagonists could result from their inhibitory effects on the AT(1)-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 prointlammatory-redox AT(1)-mediated pathway, in such mechanism, AT(1) activation leads to the aortic release of tumor necrosis factor-alpha 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 AT(1)-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. (C) 2015 Elsevier B.V. All rights reserved. (AU)

• Processo FAPESP: 14/17740-0 - Planejamento, desenvolvimento e avaliação farmacológica de novos antagonistas de receptores para hidrocarbonetos arila (AhR) candidatos a fármacos ateroprotetores
• Beneficiário: Larissa Pernomian
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 12/00640-7 - Estudo das consequências do processo inflamatório induzido por receptores AT1 durante aterosclerose sobre o eixo ECA2 - angiotensina-(1-7) -Mas em aorta de camundongo e da participação de receptores Mas nos efeitos vaso- e ateroprotetores de losartan
• Beneficiário: Larissa Pernomian
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/09019-3 - Consequências da dislipidemia sobre os eixos ECA - Ang II - AT1 e ECA2 - Ang-(1-7) - mas do sistema angiotensinérgico em aorta de camundongos LDLr knockout jovens e adultos
• Beneficiário: Ana Maria de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Regular