Aldosterone impairs mitochondrial function in human cardiac fibroblasts via A-kinase anchor protein 12

Ibarrola Ulzurrun, Jaime Francisco; Sádaba Sagredo, Rafael; Martínez Martínez, Ernesto; García Peña, Amaia; Gaínza Calleja, Alicia

Publication:
Aldosterone impairs mitochondrial function in human cardiac fibroblasts via A-kinase anchor protein 12

dc.contributor.author	Ibarrola Ulzurrun, Jaime Francisco
dc.contributor.author	Sádaba Sagredo, Rafael
dc.contributor.author	Martínez Martínez, Ernesto
dc.contributor.author	García Peña, Amaia
dc.contributor.author	Gaínza Calleja, Alicia
dc.contributor.department	Ciencias de la Salud	es_ES
dc.contributor.department	Osasun Zientziak	eu
dc.date.accessioned	2020-11-12T13:59:55Z
dc.date.available	2020-11-12T13:59:55Z
dc.date.issued	2018
dc.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.	en
dc.description.sponsorship	This work was supported by: Miguel Servet contract CP13/00221 from the 'Instituto de Salud Carlos III-FEDER', Fondo de Investigaciones Sanitarias [PI15/02160], FIBROTARGETS project (FP7 #602904), ANR-MR focus (15-CE14-0032), Plan Estatal I+D+I 2013-2016 and Ministry of Economy and Competitiveness (SAF2016-79151-R). The Proteomics Unit of Navarrabiomed is a member of Proteored, PRB2-ISCIII, and is supported by grant PT13/0001, of the PE I+D+I 2013–2016 funded by ISCIII and FEDER.	en
dc.format.extent	11 p.
dc.format.mimetype	application/pdf	en
dc.identifier.doi	10.1038/s41598-018-25068-6
dc.identifier.issn	2045-2322
dc.identifier.uri	https://academica-e.unavarra.es/handle/2454/38628
dc.language.iso	eng	en
dc.publisher	Springer	en
dc.relation.ispartof	Scientific Reports, 2018, 8, 6801	en
dc.relation.projectID	info:eu-repo/grantAgreement/ES/1PE/SAF2016-79151-R	en
dc.relation.projectID	info:eu-repo/grantAgreement/European Commission/FP7/602904	en
dc.relation.publisherversion	https://doi.org/10.1038/s41598-018-25068-6
dc.rights	© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.	en
dc.rights.accessRights	info:eu-repo/semantics/openAccess	en
dc.rights.accessRights	Acceso abierto / Sarbide irekia	es
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/
dc.subject	Heart failure	en
dc.subject	Mechanisms of disease	en
dc.title	Aldosterone impairs mitochondrial function in human cardiac fibroblasts via A-kinase anchor protein 12	en
dc.type	info:eu-repo/semantics/article
dc.type.version	info:eu-repo/semantics/publishedVersion	en
dc.type.version	Versión publicada / Argitaratu den bertsioa	es
dspace.entity.type	Publication
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