Abstract
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.
Highlights
IntroductionA better understanding of the underlying mechanisms for the development of cardiovascular diseases (CVDs) is inevitable to prevent the progression of cardiac remodeling and failure
Due to the fact that autophagy’s role in the failing heart is still a matter of ongoing debate, we aimed to investigate the role of autophagy during cardiac dysfunction in transverse aortic constriction (TAC)-hearts and on contractility in endothelin 1 (ET-1) treated cardiomyocytes
We aimed to investigate whether hypertrophy-reduced in autophagy
Summary
A better understanding of the underlying mechanisms for the development of CVDs is inevitable to prevent the progression of cardiac remodeling and failure. Pressure overload in the heart initially increases left ventricular mass and cell size to elevate force of contraction, which can progress to left ventricular hypertrophy [2], high serum levels of natriuretic peptides get released, brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) [3], cardiomyocyte contractility declines and the formation of reactive oxygen species increases (ROS) [4], all of which resulting in heart failure (HF) [5,6,7]. Since cardiomyocytes are widely accepted as post-mitotic cells, functional and balanced proteostasis is essential to maintain cardiac homeostasis and performance. Degradation systems, like the ubiquitin-proteasomal system or autophagy-lysosomal pathway (ALP), avoid the accumulation of highly modified, crosslinked and defective proteins by intracellular turnover [8,9]
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