The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium

Mineralocorticoid receptor (MR) antagonists decreasemorbidity andmortality in heart failure patients forwhom oxidative stress is usual; however, the underlying mechanism for this protection is unclear. Since aldosterone stimulates reactive oxygen species (ROS) production in several tissues,we explor...

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Detalles Bibliográficos
Autores principales:	Nolly, Mariela Beatriz, Caldiz, Claudia Irma, Yeves, Alejandra del Milagro, Villa Abrille, María Celeste, Morgan, Patricio Eduardo, Mondaca, Nicolás Amado, Portiansky, Enrique Leo, Chiappe de Cingolani, Gladys Ethel, Cingolani, Horacio Eugenio, Ennis, Irene Lucía
Formato:	Articulo
Lenguaje:	Inglés
Publicado:	2014
Materias:	Ciencias Médicas Mineralocorticoid receptor Oxidative stress siRNA Transactivation
Acceso en línea:	http://sedici.unlp.edu.ar/handle/10915/105834
Aporte de:	SEDICI (UNLP) de Universidad Nacional de La Plata

id	I19-R120-10915-105834
record_format	dspace
institution	Universidad Nacional de La Plata
institution_str	I-19
repository_str	R-120
collection	SEDICI (UNLP)
language	Inglés
topic	Ciencias Médicas Mineralocorticoid receptor Oxidative stress siRNA Transactivation
spellingShingle	Ciencias Médicas Mineralocorticoid receptor Oxidative stress siRNA Transactivation Nolly, Mariela Beatriz Caldiz, Claudia Irma Yeves, Alejandra del Milagro Villa Abrille, María Celeste Morgan, Patricio Eduardo Mondaca, Nicolás Amado Portiansky, Enrique Leo Chiappe de Cingolani, Gladys Ethel Cingolani, Horacio Eugenio Ennis, Irene Lucía The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium
topic_facet	Ciencias Médicas Mineralocorticoid receptor Oxidative stress siRNA Transactivation
description	Mineralocorticoid receptor (MR) antagonists decreasemorbidity andmortality in heart failure patients forwhom oxidative stress is usual; however, the underlying mechanism for this protection is unclear. Since aldosterone stimulates reactive oxygen species (ROS) production in several tissues,we explored its effect and the intracellular pathway involved in the rat myocardium. Aldosterone dose-dependently increased O2 − production inmyocardial slices. At 10 nmol/L, aldosterone increased O2 − to 165 ± 8.8% of control, an effect prevented not only by the MR antagonists eplerenone and spironolactone (107 ± 7.8 and 103 ± 5.3%, respectively) but also by AG1478 (105 ± 8.0%), antagonist of the EGF receptor (EGFR). Similar results were obtained by silencing MR expression through the direct intramyocardial injection of a lentivirus coding for a siRNA against the MR. The aldosterone effect on O2 − production was mimicked by the mKATP channel opener diazoxide and blocked by preventing its opening with 5-HD and glibenclamide, implicating the mitochondria as the source of O2 −. Inhibiting the respiratory chainwith rotenone or mitochondrial permeability transition (MPT)with cyclosporine A or bongkrekic acid also canceled aldosterone-induced O2 − production. In addition, aldosterone effect depended on NADPH oxidase and phosphoinositide 3-kinase activation, as apocynin and wortmannin, respectively, inhibited it. EGF (0.1 μg/ mL) similarly increased O2 −, although in this case MR antagonists had no effect, suggesting that EGFR transactivation occurred downstream from MR activation. Inhibition of mKATP channels, the respiratory chain, or MPT did not prevent Akt phosphorylation, supporting that it happened upstreamof the mitochondria. Importantly, cardiomyocytes were confirmed as a source of aldosterone induced mitochondrial ROS production in experiments performed in isolated cardiac myocytes. These results allowus to speculate that the beneficial effects ofMRantagonists in heart failure may be related to a decrease in oxidative stress.
format	Articulo Articulo
author	Nolly, Mariela Beatriz Caldiz, Claudia Irma Yeves, Alejandra del Milagro Villa Abrille, María Celeste Morgan, Patricio Eduardo Mondaca, Nicolás Amado Portiansky, Enrique Leo Chiappe de Cingolani, Gladys Ethel Cingolani, Horacio Eugenio Ennis, Irene Lucía
author_facet	Nolly, Mariela Beatriz Caldiz, Claudia Irma Yeves, Alejandra del Milagro Villa Abrille, María Celeste Morgan, Patricio Eduardo Mondaca, Nicolás Amado Portiansky, Enrique Leo Chiappe de Cingolani, Gladys Ethel Cingolani, Horacio Eugenio Ennis, Irene Lucía
author_sort	Nolly, Mariela Beatriz
title	The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium
title_short	The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium
title_full	The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium
title_fullStr	The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium
title_full_unstemmed	The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium
title_sort	signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium
publishDate	2014
url	http://sedici.unlp.edu.ar/handle/10915/105834
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The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium

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