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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2018-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-018-25068-6 |
| _version_ | 1818993626055704576 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T20:45:02Z |
| format | Article |
| id | doaj.art-a9c8efc7146c4ee994e0f69162a05f84 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T20:45:02Z |
| publishDate | 2018-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a9c8efc7146c4ee994e0f69162a05f842022-12-21T19:27:03ZengNature PortfolioScientific Reports2045-23222018-05-018111110.1038/s41598-018-25068-6Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12Jaime Ibarrola0Rafael Sadaba1Ernesto Martinez-Martinez2Amaia Garcia-Peña3Vanessa Arrieta4Virginia Alvarez5Amaya Fernández-Celis6Alicia Gainza7Victoria Cachofeiro8Enrique Santamaria9Joaquin Fernandez-Irigoyen10Frederic Jaisser11Natalia Lopez-Andres12Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNACardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNACardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNACardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNACardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNACardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNACardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNACardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNADepartment of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Ciber de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos IIIProteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNAProteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNAINSERM, Centre d’Investigations Cliniques-Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCTCardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNAAbstract 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.https://doi.org/10.1038/s41598-018-25068-6 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-018-25068-6 |
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