Suppression of autophagy induces senescence in the heart.

Autor: Zhai P; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103., Sung EA; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103., Shiheido-Watanabe Y; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103., Takayama K; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103., Tian Y; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103., Sadoshima J; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103. Electronic address: sadoshju@njms.rutgers.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2024 Oct; Vol. 195, pp. 83-96. Date of Electronic Publication: 2024 Aug 06.
DOI: 10.1016/j.yjmcc.2024.08.001
Abstrakt: Aging is a critical risk factor for heart disease, including ischemic heart disease and heart failure. Cellular senescence, characterized by DNA damage, resistance to apoptosis and the senescence-associated secretory phenotype (SASP), occurs in many cell types, including cardiomyocytes. Senescence precipitates the aging process in surrounding cells and the organ through paracrine mechanisms. Generalized autophagy, which degrades cytosolic materials in a non-selective manner, is decreased during aging in the heart. This decrease causes deterioration of cellular quality control mechanisms, facilitates aging and negatively affects lifespan in animals, including mice. Although suppression of generalized autophagy could promote senescence, it remains unclear whether the suppression of autophagy directly stimulates senescence in cardiomyocytes, which, in turn, promotes myocardial dysfunction in the heart. We addressed this question using mouse models with a loss of autophagy function. Suppression of general autophagy in cardiac-specific Atg7 knockout (Atg7cKO) mice caused accumulation of senescent cardiomyocytes. Induction of senescence via downregulation of Atg7 was also observed in chimeric Atg7 cardiac-specific KO mice and cultured cardiomyocytes in vitro, suggesting that the effect of autophagy suppression upon induction of senescence is cell autonomous. ABT-263, a senolytic agent, reduced the number of senescent myocytes and improved cardiac function in Atg7cKO mice. Suppression of autophagy and induction of senescence were also observed in doxorubicin-treated hearts, where reactivation of autophagy alleviated senescence in cardiomyocytes and cardiac dysfunction. These results suggest that suppression of general autophagy directly induces senescence in cardiomyocytes, which in turn promotes cardiac dysfunction.
Competing Interests: Declaration of competing interest J.S. serves as Senior Consulting Editor of the JMCC.
(Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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