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

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• 作者：Larissa Pernomian^a ; ^{l.pernomian@usp.br" class="auth_mail" title="E-mail the corresponding author} ; Alejandro F. do Prado^b ; Mayara S. Gomes^c ; Laena Pernomian^b ; Carlos H.T.P. da Silva^a ; Raquel F. Gerlach^d ; Ana M. de Oliveira^c
• 关键词：Early atherosclerosis ; AT1 receptors ; Angiotensin-converting-enzyme 2 ; Angiotensin-(1-7) ; MAS receptors ; Candesartan
• 刊名：European Journal of Pharmacology
• 出版年：2015
• 出版时间：5 October 2015
• 年：2015
• 卷：764
• 期：Complete
• 页码：173-188
• 全文大小：6180 K

文摘

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-伪, 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.