Autophagy as a mechanism for myolysis of cardiomyocytes in mitral regurgitation

Chen, Mien‐Cheng; Chang, Jen‐Ping; Wang, Yahui; Liu, Wenhao; Ho, Wan-Chun; Chang, Hsueh‐Wen

doi:10.1111/j.1365-2362.2010.02410.x

Cited by 27 publications

(28 citation statements)

References 24 publications

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“…Ins(1,4,5)P 3 generation increases acutely under conditions of post-ischemic reperfusion [43] and chronically in dilated fibrosed atrial tissue from human and mouse [44]. Autophagy is increased in both of these circumstances, primarily as a protective mechanism [45][46][47]. It is possible that Ins(1,4,5)P 3 functions as an endogenous autophagy inhibitor under these pathological conditions.…”

Section: Discussionmentioning

confidence: 92%

Regulation of autophagy in cardiomyocytes by Ins(1,4,5)P3 and IP3-receptors

Wong

Grubb

Cooley

et al. 2013

Journal of Molecular and Cellular Cardiology

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Section: Discussionmentioning

confidence: 92%

Regulation of autophagy in cardiomyocytes by Ins(1,4,5)P3 and IP3-receptors

Wong

Grubb

Cooley

et al. 2013

Journal of Molecular and Cellular Cardiology

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“…There is ongoing debate about whether autophagy plays a beneficial or detrimental role in cardiac diseases . Excessive autophagy contributed to age‐related cardiac disease development, including heart failure, hypertension‐induced cardiac diseases, mitral regurgitation, and diabetic cardiomyopathy . Interestingly, all these cardiac diseases are recognized to represent a substrate for AF, suggesting a role for autophagic activation in AF development.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy is widely involved as a cell‐stress pathway, whose excessive activation triggers cardiac remodeling in response to degradation of essential proteins and organelles. Activation of autophagy in the heart is implicated in cardiac remodeling in mitral regurgitation and cardiac hypertrophy …”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Is Associated With Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation

Wiersma

Meijering

et al. 2017

JAHA

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BackgroundDerailment of proteostasis, the homeostasis of production, function, and breakdown of proteins, contributes importantly to the self‐perpetuating nature of atrial fibrillation (AF), the most common heart rhythm disorder in humans. Autophagy plays an important role in proteostasis by degrading aberrant proteins and organelles. Herein, we investigated the role of autophagy and its activation pathway in experimental and clinical AF.Methods and ResultsTachypacing of HL‐1 atrial cardiomyocytes causes a gradual and significant activation of autophagy, as evidenced by enhanced LC3B‐II expression, autophagic flux and autophagosome formation, and degradation of p62, resulting in reduction of Ca2+ amplitude. Autophagy is activated downstream of endoplasmic reticulum (ER) stress: blocking ER stress by the chemical chaperone 4‐phenyl butyrate, overexpression of the ER chaperone‐protein heat shock protein A5, or overexpression of a phosphorylation‐blocked mutant of eukaryotic initiation factor 2α (eIF2α) prevents autophagy activation and Ca2+‐transient loss in tachypaced HL‐1 cardiomyocytes. Moreover, pharmacological inhibition of ER stress in tachypaced Drosophila confirms its role in derailing cardiomyocyte function. In vivo treatment with sodium salt of phenyl butyrate protected atrial‐tachypaced dog cardiomyocytes from electrical remodeling (action potential duration shortening, L‐type Ca2+‐current reduction), cellular Ca2+‐handling/contractile dysfunction, and ER stress and autophagy; it also attenuated AF progression. Finally, atrial tissue from patients with persistent AF reveals activation of autophagy and induction of ER stress, which correlates with markers of cardiomyocyte damage.ConclusionsThese results identify ER stress–associated autophagy as an important pathway in AF progression and demonstrate the potential therapeutic action of the ER‐stress inhibitor 4‐phenyl butyrate.

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“…Similarly, time and AMPK‐dependent autophagy were found in canine model of AF . In another study, enhanced autophagy was found in atria originated from patient suffering from mitral regurgitation in the presence or absence of AF . However, in the aforementioned studies, the functionality of autophagic process was not studied.…”

Section: Autophagy Diabetic Cardiomyopathy and ‘Biotherapeutic’ Treamentioning

confidence: 98%

Autophagy: an adaptive physiological countermeasure to cellular senescence and ischaemia/reperfusion‐associated cardiac arrhythmias

Lekli

Haines

Balla

et al. 2016

J Cellular Molecular Medi

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Oxidative stress placed on tissues that involved in pathogenesis of a disease activates compensatory metabolic changes, such as DNA damage repair that in turn causes intracellular accumulation of detritus and ‘proteotoxic stress’, leading to emergence of ‘senescent’ cellular phenotypes, which express high levels of inflammatory mediators, resulting in degradation of tissue function. Proteotoxic stress resulting from hyperactive inflammation following reperfusion of ischaemic tissue causes accumulation of proteinaceous debris in cells of the heart in ways that cause potentially fatal arrhythmias, in particular ventricular fibrillation (VF). An adaptive response to VF is occurrence of autophagy, an intracellular bulk degradation of damaged macromolecules and organelles that may restore cellular and tissue homoeostasis, improving chances for recovery. Nevertheless, depending on the type and intensity of stressors and inflammatory responses, autophagy may become pathological, resulting in excessive cell death. The present review examines the multilayered defences that cells have evolved to reduce proteotoxic stress by degradation of potentially toxic material beginning with endoplasmic reticulum‐associated degradation, and the unfolded protein response, which are mechanisms for removal from the endoplasmic reticulum of misfolded proteins, and then progressing through the stages of autophagy, including descriptions of autophagosomes and related vesicular structures which process material for degradation and autophagy‐associated proteins including Beclin‐1 and regulatory complexes. The physiological roles of each mode of proteotoxic defence will be examined along with consideration of how emerging understanding of autophagy, along with a newly discovered regulatory cell type called telocytes, may be used to augment existing strategies for the prevention and management of cardiovascular disease.

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Autophagy as a mechanism for myolysis of cardiomyocytes in mitral regurgitation

Abstract: Induction of autophagy, but not oncosis, occurs in most cases of atrial cardiomyocytes with severe mitral and tricuspid regurgitation, even those without atrial fibrillation, and is closely associated with the development of myolysis in this disease.

Cited by 27 publications

References 24 publications

Regulation of autophagy in cardiomyocytes by Ins(1,4,5)P3 and IP3-receptors

Regulation of autophagy in cardiomyocytes by Ins(1,4,5)P3 and IP3-receptors

Endoplasmic Reticulum Stress Is Associated With Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation

Autophagy: an adaptive physiological countermeasure to cellular senescence and ischaemia/reperfusion‐associated cardiac arrhythmias

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