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Consequences of dyslipidemia on the ACE - Ang II - AT1 and ACE2 - Ang-(1-7) - mas axes from the angiotensinergic system in aorta from young and adult LDLr knockout mice

Abstract

Angiotensin II (Ang II) evokes pro-atherogenic effects by activating AT1 receptors, which subsequently releases TNF-±, that activates NAD(P)H oxidase and generates superoxide (O2-) and hydrogen peroxide (H2O2), a well-known COX2 inductor. In turn, COX2 also generates reactive oxygen species (ROS), that contribute to the dyslipidemic vascular dysfunction. Despite the atherogenic effects from ACE - Ang II - AT1 axis, the ACE2 - Angiotensin-(1-7) [Ang-(1-7)] - Mas axis evokes atheroprotective effects. Thus, the hypothesis from the present study is that the dyslipidemia, induced in young mice, would enhance the ACE - Ang II - AT1 axis in the activation of TNF-± - NAD(P)H oxidase - O2- - H2O2 - COX-2 pathway, which would impair the ACE2 - Ang-(1-7) - Mas axis, contributing to the aortic atherogenesis in adult mice. To investigate this hypothesis, LDLr knockout mice will be fed with high-fat diet and will be treated with lisinopril (ACE inhibitor), combined or not with losartan (AT1 receptor antagonist) or celecoxibe (COX2 selective inhibitor). The consequences of the dyslipidemia on the ACE - Ang II - AT1 axis in the activation of TNF-± - NAD(P)H oxidase - O2- - H2O2 - COX-2 pathway will be determined by means of immunohistochemistry for ACE, AT1 receptors, TNF-±, NAD(P)H and COX2, cumulative curves for Ang I or Ang II, and confocal microscopy to detect the ROS generation trough this pathway. The consequences of the activation of ACE - Ang II - AT1 axis on ACE2 - Ang-(1-7) - Mas axis will be determined by means of immunohistochemistry and Western blotting for ACE2 and Mas receptors, mass spectrometry to measure ACE2 activity, and curves for Ang-(1-7), after animal treatment with lisinopril, losartan and/or celecoxibe. (AU)

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Scientific publications (8)
(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; MOREIRA, JOSIMAR DORNELAS; GOMES, MAYARA SANTOS. In the View of Endothelial Microparticles: Novel Perspectives for Diagnostic and Pharmacological Management of Cardiovascular Risk during Diabetes Distress. JOURNAL OF DIABETES RESEARCH, 2018. Web of Science Citations: 0.
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, 2017. Web of Science Citations: 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, 2017. Web of Science Citations: 0.
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, 2017. Web of Science Citations: 0.
PEREIRA, PRISCILA CRISTINA; PERNOMIAN, LARISSA; COCO, HARIANE; GOMES, MAYARA SANTOS; FRANCO, JOAO JOSE; MARCHI, KATIA COLOMBO; HIPOLITO, ULISSES VILELA; UYEMURA, SERGIO AKIRA; TIRAPELLI, CARLOS RENATO; DE OLIVEIRA, ANA MARIA. Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia. European Journal of Pharmacology, v. 781, p. 1-9, JUN 15 2016. Web of Science Citations: 1.
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, OCT 5 2015. Web of Science Citations: 11.
PERNOMIAN, LAENA; PERNOMIAN, LARISSA; ARAUJO RESTINI, CAROLINA BARALDI. Counter-regulatory effects played by the ACE - Ang II-AT1 and ACE2-Ang-(1-7) - Mas axes on the reactive oxygen species-mediated control of vascular function:perspectives to pharmacological approaches in controlling vascular complications. Vasa-European Journal of Vascular Medicine, v. 43, n. 6, p. 404-414, NOV 2014. Web of Science Citations: 16.
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, 2014. Web of Science Citations: 9.

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