The role of autophagy in death of cardiomyocytes

Ikeda, Shohei; Zablocki, Daniela; Sadoshima, Junichi

doi:10.1016/j.yjmcc.2021.12.006

Cited by 58 publications

(49 citation statements)

References 58 publications

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“…Finally, it should be noted that, whereas moderate up-regulation of autophagy is often health protective, excessive autophagy, when not matched by compensatory anabolism, can lead to autophagic cell death [179][180][181]. Whereas up-regulation of autophagy appears to be beneficial in the early stages of various neurodegenerative diseases entailing accumulation of pathogenic protein complexes, it may be counterproductive in later-stage disease [182].…”

Section: Discussionmentioning

confidence: 99%

Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy

McCarty

2022

IJMS

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Macroautophagy is a “cell cleansing” process that rids cells of protein aggregates and damaged organelles that may contribute to disease pathogenesis and the dysfunctions associated with aging. Measures which boost longevity and health span in rodents typically up-regulate macroautophagy, and it has often been suggested that safe strategies which can promote this process in humans may contribute to healthful aging. The kinase ULK1 serves as a trigger for autophagy initiation, and the transcription factors TFEB, FOXO1, ATF4 and CHOP promote expression of a number of proteins which mediate macroautophagy. Nutraceutical or dietary measures which stimulate AMPK, SIRT1, eIF5A, and that diminish the activities of AKT and mTORC1, can be expected to boost the activities of these pro-autophagic factors. The activity of AMPK can be stimulated with the phytochemical berberine. SIRT1 activation may be achieved with a range of agents, including ferulic acid, melatonin, urolithin A, N1-methylnicotinamide, nicotinamide riboside, and glucosamine; correction of ubiquinone deficiency may also be useful in this regard, as may dietary strategies such as time-restricted feeding or intermittent fasting. In the context of an age-related decrease in cellular polyamine levels, provision of exogenous spermidine can boost the hypusination reaction required for the appropriate post-translational modification of eIF5A. Low-protein plant-based diets could be expected to increase ATF4 and CHOP expression, while diminishing IGF-I-mediated activation of AKT and mTORC1. Hence, practical strategies for protecting health by up-regulating macroautophagy may be feasible.

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Section: Discussionmentioning

confidence: 99%

Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy

McCarty

2022

IJMS

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“…Autophagy is an evolutionally conserved process for the degradation of long-lived and/or damaged proteins and organelles occurring in cells throughout the body [ 110 , 111 , 112 ] and during the neonatal period in particular, thus providing a necessary source of energy in various tissues [ 113 ]. Under physiological conditions, the autophagy activity in the heart remains low, aiding in the maintenance of the cell components, and is rapidly activated under pathophysiological conditions to support cardio-protection [ 114 , 115 , 116 , 117 , 118 , 119 ]. However, during the only early neonatal starvation period, autophagy in the heart is known to be activated [ 113 ].…”

Section: Characteristics Of Acmsmentioning

confidence: 99%

Atypically Shaped Cardiomyocytes (ACMs): The Identification, Characterization and New Insights into a Subpopulation of Cardiomyocytes

Omatsu‐Kanbe

Fukunaga

et al. 2022

Biomolecules

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In the adult mammalian heart, no data have yet shown the existence of cardiomyocyte-differentiable stem cells that can be used to practically repair the injured myocardium. Atypically shaped cardiomyocytes (ACMs) are found in cultures of the cardiomyocyte-removed fraction obtained from cardiac ventricles from neonatal to aged mice. ACMs are thought to be a subpopulation of cardiomyocytes or immature cardiomyocytes, most closely resembling cardiomyocytes due to their spontaneous beating, well-organized sarcomere and the expression of cardiac-specific proteins, including some fetal cardiac gene proteins. In this review, we focus on the characteristics of ACMs compared with ventricular myocytes and discuss whether these cells can be substitutes for damaged cardiomyocytes. ACMs reside in the interstitial spaces among ventricular myocytes and survive under severely hypoxic conditions fatal to ventricular myocytes. ACMs have not been observed to divide or proliferate, similar to cardiomyocytes, but they maintain their ability to fuse with each other. Thus, it is worthwhile to understand the role of ACMs and especially how these cells perform cell fusion or function independently in vivo. It may aid in the development of new approaches to cell therapy to protect the injured heart or the clarification of the pathogenesis underlying arrhythmia in the injured heart.

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“…Controlled by autophagy-related proteins (Atgs) and microtubule-associated protein 1 light chain 3 (LC3), the autophagy machinery engulfs cargos via double membrane-surrounded autophagic vesicles (autophagosomes), which culminates in lysosomal degradation through the fusion with lysosomes (autolysosomes) 2 . Autophagy plays an essential role in CR to maintain cardiac function and cellular homeostasis or to mediate cell death in the heart 3 , 4 . Mitochondrial damage is a major intracellular change and is considered cytotoxic to cardiomyocytes, the main cell type of the heart 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Autophagy plays an essential role in CR to maintain cardiac function and cellular homeostasis or to mediate cell death in the heart 3 , 4 . Mitochondrial damage is a major intracellular change and is considered cytotoxic to cardiomyocytes, the main cell type of the heart 4 . Mitophagy targeting damaged mitochondria has been reported to exacerbate the propensity for spontaneous CR in laboratory animals and is suggested to be a potential target for reversing CR 3 .…”

Section: Introductionmentioning

confidence: 99%

Cardiomyocytic FoxP3 is involved in Parkin-mediated mitophagy during cardiac remodeling and the regulatory role of triptolide

Pan¹,

Xiong²,

Hong³

et al. 2022

Theranostics

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Rationale: Forkhead/winged helix transcriptional factor P3 (FoxP3) is a well-studied transcription factor that maintains the activity of T cells, but whether cardiomyocytic FoxP3 participates in cardiac remodeling (CR) remains unclear. The present study was to investigate the role of cardiomyocytic FoxP3 in CR from the perspective of mitophagy. Methods: CR was induced by angiotensin II (AngII) in vitro , or by isoproterenol (Iso) in vivo using male C57 mice or FoxP3 DTR mice. Histological changes were observed by hematoxylin-eosin and Masson staining. Molecular changes were detected by immunohistochemistry, immunofluorescence, immunoblotting, and real-time PCR. Mitophagy was shaped by transmission electron microscopy and co-localization. The mRNA expression was operated by siRNA or adeno associated virus (AAV). Molecular interactions were detected by co-localization, immunoprecipitation (IP), and chromatin IP. Results: The expression and nuclear translocation of cardiomyocytic FoxP3 were downregulated in CR, while they were upregulated after triptolide (TP) treatment. In left ventricle (LV) remodeling in mice, autophagy was activated continuously in the myocardium, and TP significantly attenuated it. AngII induced massive mitophagy characterized by the activation of autophagy regulatory protein 5 (Atg5)-dependent autophagic flux. Critically, Parkin was identified as the main adaptor mediated myocardial mitophagy and was responsible for the effect of TP. Moreover, FoxP3 was responsible for the downregulation of Parkin and inhibited AngII-induced cardiac mitophagy. We found that mitophagy increased significantly and the inhibition of TP treatment reversed completely in FoxP3-deficient LVs. Mechanistically, FoxP3 interacted with a motif located downstream of the activating transcription 4 (ATF4)-binding motif involved in the promoter of Parkin and hijacked free nuclear ATF4 to decrease Parkin mRNA expression in CR. Conclusion: Cardiomyocytic FoxP3 could negatively regulate Parkin-mediated mitophagy in CR, and restoring cardiomyocytic FoxP3 activity provided a cardioprotective strategy by inhibiting excessive cardiac mitophagy.

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The role of autophagy in death of cardiomyocytes

Cited by 58 publications

References 58 publications

Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy

Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy

Atypically Shaped Cardiomyocytes (ACMs): The Identification, Characterization and New Insights into a Subpopulation of Cardiomyocytes

Cardiomyocytic FoxP3 is involved in Parkin-mediated mitophagy during cardiac remodeling and the regulatory role of triptolide

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