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Study of the consequences of the inflammatory process induced by AT1 receptors during atherosclerosis on the ACE2 - angiotensin-(1-7) - Mas axis in mouse aorta and the involvement of Mas receptors in the vaso- and atheroprotective effects of losartan

Grant number: 12/00640-7
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2012
Effective date (End): February 28, 2015
Field of knowledge:Biological Sciences - Pharmacology
Principal researcher:Ana Maria de Oliveira
Grantee:Larissa Pernomian
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


By activating AT1 receptors, angiotensin II (Ang II) induces the endothelial release of tumor necrosis factor-± (TNF-±), which evokes pro-atherogenic effects mediated by NAD(P)H oxidase-derived superoxide anion (O2-). Despite the pro-atherogenic effects mediated by AT1 receptors, the ACE2 - Angiotensin-(1-7) [Ang-(1-7)] - Mas axis evokes vaso-and atheroprotective effects. In fact, the chronic treatment with Ang-(1-7) attenuates the atherosclerotic endothelial dysfunction and the atherogenesis. Thus, we hypothesized that atherosclerosis would impair the functionality of the ACE2 - Ang-(1-7) - Mas axis in mouse aorta by a mechanism mediated by O2- derived from NAD(P)H oxidase activated by TNF-±, which would being released after the activation of AT1 receptors. Based on this, the treatment with the AT1 antagonist losartan would restore the functionality of the ACE2 - Ang-(1-7) - Mas axis and produce Mas receptors-dependent vaso- and atheroprotective effects. In order to investigate this hypothesis, low density lipoprotein receptor deficient mice (LDL-/-) will be fed with a high-fat diet. ACE2 activity in the Ang-(1-7) generation and the Mas receptors-mediated relaxation will be determined in thoracic aorta in the absence or presence of losartan, antibody against TNF-±, apocinin [NAD(P)H oxidase inhibitor] or tiron (O2- scavenger). The vaso- and atheroprotective effects induced by losartan will be studied in aorta from high-fat diet-fed LDL-/- mice treated with losartan, combined or not with the Mas antagonist A779, by arterial reactivity studies using acetylcholine and histological analysis of atherosclerotic lesions and adhesion molecules. (AU)

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Scientific publications (11)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PERNOMIAN, LARISSA; GIMENES, LILIAN R.; GOMES, MAYARA S.; DO VALE, BRUNO N.; CARDOSO, CRISTINA R. B.; DE OLIVEIRA, ANA M.; MOREIRA, JOSIMAR D.. Endothelinergic Contractile Hyperreactivity in Rat Contralateral Carotid to Balloon Injury: Integrated Role for ETB Receptors and Superoxide Anion. BIOMED RESEARCH INTERNATIONAL, . (13/08216-2, 12/00640-7, 14/17740-0, 12/09019-3, 09/01005-0)
PERNOMIAN, LARISSA; PERNOMIAN, LAENA; GOMES, MAYARA S.; DA SILVA, CARLOS H. T. P.. Pharmacological significance of the interplay between angiotensin receptors: MAS receptors as putative final mediators of the effects elicited by angiotensin ATi receptors antagonists. European Journal of Pharmacology, v. 769, p. 143-146, . (13/08216-2, 12/00640-7, 11/11205-7, 14/17740-0)
PERNOMIAN, LARISSA; GOMES, MAYARA SANTOS; MOREIRA, JOSIMAR DORNELAS; TOMICH DE PAULA DA SILVA, CARLOS HENRIQUE; CAMPOS ROSA, JOAQUIN MARIA; DE BARROS CARDOSO, CRISTINA RIBEIRO. New Horizons on Molecular Pharmacology Applied to Drug Discovery: When Resonance Overcomes Radioligand Binding. CURRENT RADIOPHARMACEUTICALS, v. 10, n. 1, p. 16-20, . (12/00640-7, 14/17740-0, 12/09019-3)
PERNOMIAN, LARISSA; GOMES, MAYARA S.; PERNOMIAN, LAENA; MOREIRA, RAFAEL P.; CORREA, FERNANDO M. A.; DE OLIVEIRA, ANA M.. Vasoprotective effects of neurocompensatory response to balloon injury during diabetes involve the improvement of Mas signaling by TGF beta(1) activation. VASCULAR PHARMACOLOGY, v. 64, p. 36-48, . (09/01005-0, 11/11205-7, 14/17740-0, 13/08216-2, 12/00640-7)
PERNOMIAN, LARISSA; GOMES, MAYARA SANTOS; ARAUJO RESTINI, CAROLINA BARALDI; DE OLIVEIRA, ANA MARIA. Mas-Mediated Antioxidant Effects Restore the Functionality of Angiotensin Converting Enzyme 2-Angiotensin-(1-7)-Mas Axis in Diabetic Rat Carotid. BIOMED RESEARCH INTERNATIONAL, . (12/00640-7, 09/01005-0, 12/09019-3)
PERNOMIAN, LARISSA; GOMES, MAYARA SANTOS; ARAUJO RESTINI, CAROLINA BARALDI; PUPO, ANDRE SAMPAIO; DE OLIVEIRA, ANA MARIA. Cross-talk with (2)-adrenoceptors enhances ligand affinity properties from endothelial alpha(1D)-adrenoceptors that mediates carotid relaxation. Journal of Pharmacy and Pharmacology, v. 65, n. 9, p. 1337-1346, . (12/00640-7)
PERNOMIAN, LARISSA; GOMES, MAYARA S.; CORREA, FERNANDO M. A.; RESTINI, CAROLINA B. A.; RAMALHO, LEANDRA N. Z.; DE OLIVEIRA, ANA M.. Diabetes confers a vasoprotective role to the neurocompensatory response elicited by carotid balloon injury: Consequences on contralateral carotid tone and blood flow. European Journal of Pharmacology, v. 708, n. 1-3, p. 124-138, . (12/00640-7, 09/01005-0)
PERNOMIAN, LARISSA; DO PRADO, ALEJANDRO F.; GOMES, MAYARA S.; PERNOMIAN, LAENA; DA SILVA, CARLOS H. T. P.; GERLACH, RAQUEL F.; DE OLIVEIRA, ANA M.. MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. European Journal of Pharmacology, v. 764, p. 173-188, . (13/08216-2, 12/00640-7, 14/17740-0, 12/09019-3)
PERNOMIAN, LARISSA; GOMES, MAYARA S.; TOMICH DE PAULA DA SILVA, CARLOS H.; ROSA, JOAQUIN M. C.. Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists. Current Medicinal Chemistry, v. 24, n. 39, p. 4360-4367, . (12/00640-7, 13/08216-2, 14/17740-0, 12/09019-3)

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