Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility
Cardiac remodeling and contractile dysfunction are leading causes in hypertrophy-associated heart failure (HF), increasing with a population’s rising age. A hallmark of aged and diseased hearts is the accumulation of modified proteins caused by an impaired autophagy-lysosomal-pathway. Although, auto...
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MDPI AG
2021-04-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/4/805 |
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| author | Christiane Ott Tobias Jung Sarah Brix Cathleen John Iris R. Betz Anna Foryst-Ludwig Stefanie Deubel Wolfgang M. Kuebler Tilman Grune Ulrich Kintscher Jana Grune |
| author_facet | Christiane Ott Tobias Jung Sarah Brix Cathleen John Iris R. Betz Anna Foryst-Ludwig Stefanie Deubel Wolfgang M. Kuebler Tilman Grune Ulrich Kintscher Jana Grune |
| author_sort | Christiane Ott |
| collection | DOAJ |
| description | Cardiac remodeling and contractile dysfunction are leading causes in hypertrophy-associated heart failure (HF), increasing with a population’s rising age. A hallmark of aged and diseased hearts is the accumulation of modified proteins caused by an impaired autophagy-lysosomal-pathway. Although, autophagy inducer rapamycin has been described to exert cardioprotective effects, it remains to be shown whether these effects can be attributed to improved cardiomyocyte autophagy and contractility. In vivo hypertrophy was induced by transverse aortic constriction (TAC), with mice receiving daily rapamycin injections beginning six weeks after surgery for four weeks. Echocardiographic analysis demonstrated TAC-induced HF and protein analyses showed abundance of modified proteins in TAC-hearts after 10 weeks, both reduced by rapamycin. In vitro, cardiomyocyte hypertrophy was mimicked by endothelin 1 (ET-1) and autophagy manipulated by silencing Atg5 in neonatal cardiomyocytes. ET-1 and siAtg5 decreased Atg5–Atg12 and LC3-II, increased natriuretic peptides, and decreased amplitude and early phase of contraction in cardiomyocytes, the latter two evaluated using ImageJ macro Myocyter recently developed by us. ET-1 further decreased cell contractility in control but not in siAtg5 cells. In conclusion, ET-1 decreased autophagy and cardiomyocyte contractility, in line with siAtg5-treated cells and the results of TAC-mice demonstrating a crucial role for autophagy in cardiomyocyte contractility and cardiac performance. |
| first_indexed | 2024-03-10T12:36:43Z |
| format | Article |
| id | doaj.art-68900f2d9e064b7abd299ecead0b1856 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T12:36:43Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-68900f2d9e064b7abd299ecead0b18562023-11-21T14:12:51ZengMDPI AGCells2073-44092021-04-0110480510.3390/cells10040805Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte ContractilityChristiane Ott0Tobias Jung1Sarah Brix2Cathleen John3Iris R. Betz4Anna Foryst-Ludwig5Stefanie Deubel6Wolfgang M. Kuebler7Tilman Grune8Ulrich Kintscher9Jana Grune10Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, GermanyDepartment of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, GermanyDepartment of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, GermanyDepartment of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, GermanyDepartment of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, GermanyCardiac remodeling and contractile dysfunction are leading causes in hypertrophy-associated heart failure (HF), increasing with a population’s rising age. A hallmark of aged and diseased hearts is the accumulation of modified proteins caused by an impaired autophagy-lysosomal-pathway. Although, autophagy inducer rapamycin has been described to exert cardioprotective effects, it remains to be shown whether these effects can be attributed to improved cardiomyocyte autophagy and contractility. In vivo hypertrophy was induced by transverse aortic constriction (TAC), with mice receiving daily rapamycin injections beginning six weeks after surgery for four weeks. Echocardiographic analysis demonstrated TAC-induced HF and protein analyses showed abundance of modified proteins in TAC-hearts after 10 weeks, both reduced by rapamycin. In vitro, cardiomyocyte hypertrophy was mimicked by endothelin 1 (ET-1) and autophagy manipulated by silencing Atg5 in neonatal cardiomyocytes. ET-1 and siAtg5 decreased Atg5–Atg12 and LC3-II, increased natriuretic peptides, and decreased amplitude and early phase of contraction in cardiomyocytes, the latter two evaluated using ImageJ macro Myocyter recently developed by us. ET-1 further decreased cell contractility in control but not in siAtg5 cells. In conclusion, ET-1 decreased autophagy and cardiomyocyte contractility, in line with siAtg5-treated cells and the results of TAC-mice demonstrating a crucial role for autophagy in cardiomyocyte contractility and cardiac performance.https://www.mdpi.com/2073-4409/10/4/805rapamycinneonatal cardiomyocyte contractilityTAChypertrophyautophagysiAtg5 |
| spellingShingle | Christiane Ott Tobias Jung Sarah Brix Cathleen John Iris R. Betz Anna Foryst-Ludwig Stefanie Deubel Wolfgang M. Kuebler Tilman Grune Ulrich Kintscher Jana Grune Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility Cells rapamycin neonatal cardiomyocyte contractility TAC hypertrophy autophagy siAtg5 |
| title | Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility |
| title_full | Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility |
| title_fullStr | Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility |
| title_full_unstemmed | Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility |
| title_short | Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility |
| title_sort | hypertrophy reduced autophagy causes cardiac dysfunction by directly impacting cardiomyocyte contractility |
| topic | rapamycin neonatal cardiomyocyte contractility TAC hypertrophy autophagy siAtg5 |
| url | https://www.mdpi.com/2073-4409/10/4/805 |
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