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Article

Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility

1
Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany
2
DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
3
Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitaetsmedizin, 10115 Berlin, Germany
4
Institute of Physiology, Charité-Universitaetsmedizin, 10115 Berlin, Germany
5
German Center for Diabetes Research, 85764 München-Neuherberg, Germany
6
Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany
7
Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Andreas Beyer
Cells 2021, 10(4), 805; https://doi.org/10.3390/cells10040805
Received: 22 February 2021 / Revised: 29 March 2021 / Accepted: 1 April 2021 / Published: 4 April 2021
(This article belongs to the Special Issue Vascular Autophagy in Health and Disease)
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. View Full-Text
Keywords: rapamycin; neonatal cardiomyocyte contractility; TAC; hypertrophy; autophagy; siAtg5 rapamycin; neonatal cardiomyocyte contractility; TAC; hypertrophy; autophagy; siAtg5
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MDPI and ACS Style

Ott, C.; Jung, T.; Brix, S.; John, C.; Betz, I.R.; Foryst-Ludwig, A.; Deubel, S.; Kuebler, W.M.; Grune, T.; Kintscher, U.; Grune, J. Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility. Cells 2021, 10, 805. https://doi.org/10.3390/cells10040805

AMA Style

Ott C, Jung T, Brix S, John C, Betz IR, Foryst-Ludwig A, Deubel S, Kuebler WM, Grune T, Kintscher U, Grune J. Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility. Cells. 2021; 10(4):805. https://doi.org/10.3390/cells10040805

Chicago/Turabian Style

Ott, Christiane, Tobias Jung, Sarah Brix, Cathleen John, Iris R. Betz, Anna Foryst-Ludwig, Stefanie Deubel, Wolfgang M. Kuebler, Tilman Grune, Ulrich Kintscher, and Jana Grune. 2021. "Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility" Cells 10, no. 4: 805. https://doi.org/10.3390/cells10040805

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