Cardiomyocyte autophagy and cancer chemotherapy

Li, Dan L.; Hill, Joseph A.

doi:10.1016/j.yjmcc.2013.11.007

Cited by 53 publications

(47 citation statements)

References 84 publications

(113 reference statements)

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“…Previous studies have addressed the possible contribution of changes in autophagic flux to doxorubicin cardiotoxicity; their findings, however, are conflicting 43, 44 . Autophagy has been reported to be either increased 8–12 or decreased 10, 13, 14 , based on in vivo and/or in vitro analyses.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

et al. 2016

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Background The clinical use of doxorubicin is limited by cardiotoxicity. Histopathologic changes include interstitial myocardial fibrosis and appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Methods and Results Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity due to haploinsufficiency for Beclin 1. Beclin 1+/− mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals over-expressing Beclin 1 manifested an amplified cardiotoxic response. Conclusions Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.

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Section: Discussionmentioning

confidence: 99%

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

et al. 2016

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“…Previous studies have indicated a unique role for defective cardiomyocyte autophagy in various cardiac anomalies such as cardiomyopathy and heart failure, as well as premature cardiac aging (68–71). Basal autophagy and autophagic flux are crucial for cardiomyocyte homeostasis (72). Cardiomyocyte-specific Atg5 knockout mice developed dilated cardiomyopathy in adulthoods (71).…”

Section: Discussionmentioning

confidence: 99%

mTOR-Independent autophagy inducer trehalose rescues against insulin resistance-induced myocardial contractile anomalies: Role of p38 MAPK and Foxo1

Wang

Ren

2016

Pharmacological Research

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Insulin resistance is associated with cardiovascular diseases although the precise mechanisms remain elusive. Akt2, a critical member of the Akt family, plays an essential role in insulin signaling. This study was designed to examine the effect of trehalose, an mTOR-independent autophagy inducer, on myocardial function in an Akt2 knockout-induced insulin resistance model. Adult WT and Akt2 knockout (Akt2−/−) mice were administered trehalose (1 mg/g/day, i.p.) for two days and were then given 2% trehalose in drinking water for two more months. Echocardiographic and myocardial mechanics, intracellular Ca2+ properties, glucose tolerance, and autophagy were assessed. Apoptosis and ER stress were evaluated using TUNEL staining, Caspase 3 assay and Western blot. Autophagy and autophagy flux were examined with a focus on p38 mitogen activated protein kinase (MAPK), Forkhead box O (Foxo1) and Akt. Akt2 ablation impaired glucose tolerance, myocardial geometry and function accompanied with pronounced apoptosis, ER stress and dampened autophagy, the effects of which were ameliorated by trehalose treatment. Inhibition of lysosomal activity using bafilomycin A1 negated trehalose–induced induction of autophagy (LC3B–II and p62). Moreover, phosphorylation of p38 MAPK and Foxo1 were upregulated in Akt2−/− mice, the effect of which was attenuated by trehalose. Phosphorylation of Akt was suppressed in Akt2−/− mice and was unaffected by trehalose. In vitro findings revealed that the p38 MAPK activator anisomycin and the Foxo1 inhibitor (through phosphorylation) AS1842856 effectively masked trehalose-offered beneficial cardiomyocyte contractile response against Akt2 ablation. These data suggest that trehalose may rescue against insulin resistance-induced myocardial contractile defect and apoptosis, via autophagy associated with dephosphorylation of p38 MAPK and Foxo1 without affecting phosphorylation of Akt.

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“…Autophagy, an evolutionally conserved process of controlled cellular cannibalization, plays a vital role in cardiac physiology. Perturbations in cardiomyocyte autophagy contribute to the pathogenesis of a wide range of cardiac diseases, many of which culminate in heart failure [10]. LC3 is the only known protein that is specifically associated with all types of autophagic membranes, including phagophores, autophagosomes and autolysosomes [10].…”

Section: Introductionmentioning

confidence: 99%

“…Perturbations in cardiomyocyte autophagy contribute to the pathogenesis of a wide range of cardiac diseases, many of which culminate in heart failure [10]. LC3 is the only known protein that is specifically associated with all types of autophagic membranes, including phagophores, autophagosomes and autolysosomes [10]. Therefore, the amount of LC3-II correlates well with the number of autophagosomes, which provides a good index of autophagy induction [9].…”

Section: Introductionmentioning

confidence: 99%

Effects of Hypoxia on Oxidative Stress, Autophagy and Apoptosis in Cardiomyocytes

Feng¹,

Shao²,

Jiao³

et al. 2019

ABC

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Coronary heart disease (CHD) is a hypoxia related disease. However, the relationship of the hypoxia-induced oxidative stress, autophagy and apoptosis in cardiomyocyte remains unclear. In this study, we used CoCl 2 to mimic hypoxic conditions in H9c2 cardiomyocytes and study the effects of CoCl 2-induced hypoxia on oxidative stress, apoptosis and autophagy, as well as the relationships among these processes. Cell viability and levels of ROS, LC3-II, p62, caspase-3 and PARP were assessed. The viability and morphology of cardiomyocytes were affected by hypoxia, and hypoxia enhanced levels of ROS and the levels of the LC3-II, p62, caspase-3 and PARP proteins in H9c2 cells in a dose-dependent manner. ROS levels rise gradually in the presence of hypoxia; however, it shrinks when hypoxia reaches a certain level. Caspase-3 and PARP levels were raised with the increasing of hypoxia level. Enhanced level of LC3 and decreased levels of p62 in hypoxic cells indicate that autophagy levels are in accord with hypoxia. Based on these results, hypoxia induces oxidative stress, apoptosis and autophagy in cardiomyocytes. Autophagy is a double-edged sword. At a low level, autophagy can resist oxidative stress and protect cardiomyocytes from oxidative stress, while high level autophagy can promote apoptosis of cardiomyocytes.

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Cardiomyocyte autophagy and cancer chemotherapy

Cited by 53 publications

References 84 publications

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification

mTOR-Independent autophagy inducer trehalose rescues against insulin resistance-induced myocardial contractile anomalies: Role of p38 MAPK and Foxo1

Effects of Hypoxia on Oxidative Stress, Autophagy and Apoptosis in Cardiomyocytes

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