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Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity.

ABSTRACT: Homeostatic regulation of cardiomyocytes plays a crucial role in maintaining the normal physiological activity of cardiac tissue. Severe cardiotoxicity results in cardiac diseases including but not limited to arrhythmia, myocardial infarction and myocardial hypertrophy. Drug-induced cardiotoxicity limits or forbids further use of the implicated drugs. Such drugs that are currently available in the clinic include anti-tumor drugs (doxorubicin, cisplatin, trastuzumab, etc.), antidiabetic drugs (rosiglitazone and pioglitazone), and an antiviral drug (zidovudine). This review focused on cardiomyocyte death forms and related mechanisms underlying clinical drug-induced cardiotoxicity, including apoptosis, autophagy, necrosis, necroptosis, pryoptosis, and ferroptosis. The key proteins involved in cardiomyocyte death signaling were discussed and evaluated, aiming to provide a theoretical basis and target for the prevention and treatment of drug-induced cardiotoxicity in the clinical practice.

SUBMITTER: Ma W

PROVIDER: S-EPMC7283551 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity.

Ma Wanjun W Wei Shanshan S Zhang Bikui B Li Wenqun W

Frontiers in cell and developmental biology 20200603

Homeostatic regulation of cardiomyocytes plays a crucial role in maintaining the normal physiological activity of cardiac tissue. Severe cardiotoxicity results in cardiac diseases including but not limited to arrhythmia, myocardial infarction and myocardial hypertrophy. Drug-induced cardiotoxicity limits or forbids further use of the implicated drugs. Such drugs that are currently available in the clinic include anti-tumor drugs (doxorubicin, cisplatin, trastuzumab, etc.), antidiabetic drugs (ro ...[more]

PMID: 32582710

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Project description:Hypoxia-inducible pro-death protein BNIP3 (BCL-2/adenovirus E1B 19-kDa interacting protein 3), provokes mitochondrial permeabilization causing cardiomyocyte death in ischemia-reperfusion injury. Inhibition of autophagy accelerates BNIP3-induced cell death, by preventing removal of damaged mitochondria. We tested the hypothesis that stimulating autophagy will attenuate BNIP3-induced cardiomyocyte death. Neonatal rat cardiac myocytes (NRCMs) were adenovirally transduced with BNIP3 (or LacZ as control; at multiplicity of infection = 100); and autophagy was stimulated with rapamycin (100 nM). Cell death was assessed at 48 h. BNIP3 expression increased autophagosome abundance 8-fold and caused a 3.6-fold increase in cardiomyocyte death as compared with control. Rapamycin treatment of BNIP3-expressing cells led to further increase in autophagosome number without affecting cell death. BNIP3 expression led to accumulation of autophagosome-bound LC3-II and p62, and an increase in autophagosomes, but not autolysosomes (assessed with dual fluorescent mCherry-GFP-LC3 expression). BNIP3, but not the transmembrane deletion variant, interacted with LC3 and colocalized with mitochondria and lysosomes. However, BNIP3 did not target to lysosomes by subcellular fractionation, provoke lysosome permeabilization or alter lysosome pH. Rather, BNIP3-induced autophagy caused a decline in lysosome numbers with decreased expression of the lysosomal protein LAMP-1, indicating lysosome consumption and consequent autophagosome accumulation. Forced expression of transcription factor EB (TFEB) in BNIP3-expressing cells increased lysosome numbers, decreased autophagosomes and increased autolysosomes, prevented p62 accumulation, removed depolarized mitochondria and attenuated BNIP3-induced death. We conclude that BNIP3 expression induced autophagosome accumulation with lysosome consumption in cardiomyocytes. Forced expression of TFEB, a lysosomal biogenesis factor, restored autophagosome processing and attenuated BNIP3-induced cell death.

Dataset Information

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity.

Publications

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity.

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