Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12

Abstract Aldosterone (Aldo) contributes to mitochondrial dysfunction and cardiac oxidative stress. Using a proteomic approach, A-kinase anchor protein (AKAP)-12 has been identified as a down-regulated protein by Aldo in human cardiac fibroblasts. We aim to characterize whether AKAP-12 down-regulatio...

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Autores principales:	Jaime Ibarrola, Rafael Sadaba, Ernesto Martinez-Martinez, Amaia Garcia-Peña, Vanessa Arrieta, Virginia Alvarez, Amaya Fernández-Celis, Alicia Gainza, Victoria Cachofeiro, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Frederic Jaisser, Natalia Lopez-Andres
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a9c8efc7146c4ee994e0f69162a05f84
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spelling	oai:doaj.org-article:a9c8efc7146c4ee994e0f69162a05f842021-12-02T15:08:18ZAldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 1210.1038/s41598-018-25068-62045-2322https://doaj.org/article/a9c8efc7146c4ee994e0f69162a05f842018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25068-6https://doaj.org/toc/2045-2322Abstract Aldosterone (Aldo) contributes to mitochondrial dysfunction and cardiac oxidative stress. Using a proteomic approach, A-kinase anchor protein (AKAP)-12 has been identified as a down-regulated protein by Aldo in human cardiac fibroblasts. We aim to characterize whether AKAP-12 down-regulation could be a deleterious mechanism which induces mitochondrial dysfunction and oxidative stress in cardiac cells. Aldo down-regulated AKAP-12 via its mineralocorticoid receptor, increased oxidative stress and induced mitochondrial dysfunction characterized by decreased mitochondrial-DNA and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expressions in human cardiac fibroblasts. CRISPR/Cas9-mediated knock-down of AKAP-12 produced similar deleterious effects in human cardiac fibroblasts. CRISPR/Cas9-mediated activation of AKAP-12 blunted Aldo effects on mitochondrial dysfunction and oxidative stress in human cardiac fibroblasts. In Aldo-salt-treated rats, cardiac AKAP-12, mitochondrial-DNA and PGC-1α expressions were decreased and paralleled increased oxidative stress. In myocardial biopsies from patients with aortic stenosis (AS, n = 26), AKAP-12, mitochondrial-DNA and PGC-1α expressions were decreased as compared to Controls (n = 13). Circulating Aldo levels inversely correlated with cardiac AKAP-12. PGC-1α positively associated with AKAP-12 and with mitochondrial-DNA. Aldo decreased AKAP-12 expression, impairing mitochondrial biogenesis and increasing cardiac oxidative stress. AKAP-12 down-regulation triggered by Aldo may represent an important event in the development of mitochondrial dysfunction and cardiac oxidative stress.Jaime IbarrolaRafael SadabaErnesto Martinez-MartinezAmaia Garcia-PeñaVanessa ArrietaVirginia AlvarezAmaya Fernández-CelisAlicia GainzaVictoria CachofeiroEnrique SantamariaJoaquin Fernandez-IrigoyenFrederic JaisserNatalia Lopez-AndresNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jaime Ibarrola Rafael Sadaba Ernesto Martinez-Martinez Amaia Garcia-Peña Vanessa Arrieta Virginia Alvarez Amaya Fernández-Celis Alicia Gainza Victoria Cachofeiro Enrique Santamaria Joaquin Fernandez-Irigoyen Frederic Jaisser Natalia Lopez-Andres Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12
description	Abstract Aldosterone (Aldo) contributes to mitochondrial dysfunction and cardiac oxidative stress. Using a proteomic approach, A-kinase anchor protein (AKAP)-12 has been identified as a down-regulated protein by Aldo in human cardiac fibroblasts. We aim to characterize whether AKAP-12 down-regulation could be a deleterious mechanism which induces mitochondrial dysfunction and oxidative stress in cardiac cells. Aldo down-regulated AKAP-12 via its mineralocorticoid receptor, increased oxidative stress and induced mitochondrial dysfunction characterized by decreased mitochondrial-DNA and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expressions in human cardiac fibroblasts. CRISPR/Cas9-mediated knock-down of AKAP-12 produced similar deleterious effects in human cardiac fibroblasts. CRISPR/Cas9-mediated activation of AKAP-12 blunted Aldo effects on mitochondrial dysfunction and oxidative stress in human cardiac fibroblasts. In Aldo-salt-treated rats, cardiac AKAP-12, mitochondrial-DNA and PGC-1α expressions were decreased and paralleled increased oxidative stress. In myocardial biopsies from patients with aortic stenosis (AS, n = 26), AKAP-12, mitochondrial-DNA and PGC-1α expressions were decreased as compared to Controls (n = 13). Circulating Aldo levels inversely correlated with cardiac AKAP-12. PGC-1α positively associated with AKAP-12 and with mitochondrial-DNA. Aldo decreased AKAP-12 expression, impairing mitochondrial biogenesis and increasing cardiac oxidative stress. AKAP-12 down-regulation triggered by Aldo may represent an important event in the development of mitochondrial dysfunction and cardiac oxidative stress.
format	article
author	Jaime Ibarrola Rafael Sadaba Ernesto Martinez-Martinez Amaia Garcia-Peña Vanessa Arrieta Virginia Alvarez Amaya Fernández-Celis Alicia Gainza Victoria Cachofeiro Enrique Santamaria Joaquin Fernandez-Irigoyen Frederic Jaisser Natalia Lopez-Andres
author_facet	Jaime Ibarrola Rafael Sadaba Ernesto Martinez-Martinez Amaia Garcia-Peña Vanessa Arrieta Virginia Alvarez Amaya Fernández-Celis Alicia Gainza Victoria Cachofeiro Enrique Santamaria Joaquin Fernandez-Irigoyen Frederic Jaisser Natalia Lopez-Andres
author_sort	Jaime Ibarrola
title	Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12
title_short	Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12
title_full	Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12
title_fullStr	Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12
title_full_unstemmed	Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12
title_sort	aldosterone impairs mitochondrial function in human cardiac fibroblasts via a-kinase anchor protein 12
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/a9c8efc7146c4ee994e0f69162a05f84
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Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12

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