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Role of endothelial mineralocorticoid receptor on the endothelial dysfunction and oxidative stress in cardiovascular diseases

Grant number: 14/26192-6
Support type:Scholarships abroad - Research
Effective date (Start): August 17, 2015
Effective date (End): August 16, 2016
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Ana Paula Couto Davel
Grantee:Ana Paula Couto Davel
Host: Iris Zamir Jaffe
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Local de pesquisa : Tufts University, United States  

Abstract

The mineralocorticoid receptor (MR) is a member of the steroid receptor family and a critical regulator of blood pressure (BP). For years the mechanism was thought to be exclusively mediated by the renal effects of the hormone aldosterone on sodium and water homeostasis. However, studies put forward the pathological role of vascular MR in cardiovascular diseases (CVD). Mice with specific deletion of MR in smooth muscle cells (SMC-MR-KO) exhibit decreased BP with aging, reduced myogenic tone and agonist-dependent contraction on resistance arteries, despite unchanged renal MR function; these data clearly supports a physiological role for SMC-MR in control of vascular tone and BP. Moreover, deletion of SMC-MR prevented the increase in SMC proliferation and fibrosis induced by aldosterone after wire-induced carotid injury suggesting that SMC-MR is also involved in vascular response to injury. However, the deletion of SMC-MR does not modulate the progression of plaque size and vascular inflammation induced by subpressor dosis of aldosterone in atherosclerosis-prone apolipoprotein E-knockout mice (ApoE-KO). These data support the hypothesis that there are BP-independent and SMC-MR-independent mechanisms contributing to aldosterone-induced atherosclerosis. NADPH oxidase activation and eNOS uncoupling induced by MR activation in endothelial cells (EC) are potential mechanisms mediating vascular oxidative stress and endothelial dysfunction (ED) in CVD. However, controversial effects of aldosterone on NO production have been reported; and if EC-MR affects vascular contractility, endothelial function and BP is not clear yet. In the present study we propose to use the first mouse model with specific deletion of MR in EC to address the role of EC-MR in mediating ED and oxidative stress in resistance arteries from CVD mouse models of hypertension and atherosclerosis.

Scientific publications (4)
(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)
LU, QING; DAVEL, ANA P.; MCGRAW, ADAM P.; RAO, SITARA P.; NEWFELL, BRENNA G.; JAFFE, IRIS Z. PKC delta Mediates Mineralocorticoid Receptor Activation by Angiotensin II to Modulate Smooth Muscle Cell Function. Endocrinology, v. 160, n. 9, p. 2101-2114, SEP 2019. Web of Science Citations: 0.
DAVEL, ANA PAULA; JAFFE, IRIS Z.; TOSTES, RITA C.; JAISSER, FREDERIC; DE CHANTEMELE, ERIC J. BELIN. New roles of aldosterone and mineralocorticoid receptors in cardiovascular disease: translational and sex-specific effects. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 315, n. 4, p. H989-H999, OCT 2018. Web of Science Citations: 5.
DAVEL, ANA P.; LU, QING; MOSS, M. ELIZABETH; RAO, SITARA; ANWAR, IMRAN J.; DUPONT, JENNIFER J.; JAFFE, IRIS Z. Sex-Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors. JOURNAL OF THE AMERICAN HEART ASSOCIATION, v. 7, n. 4 FEB 20 2018. Web of Science Citations: 18.
DAVEL, ANA P.; ANWAR, IMRAN J.; JAFFE, IRIS Z. The endothelial mineralocorticoid receptor: mediator of the switch from vascular health to disease. CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION, v. 26, n. 2, p. 97-104, MAR 2017. Web of Science Citations: 16.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.