Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration

被引：155

作者：

Abdullah, Chowdhury S. ^{[1
]}

Alam, Shafiul ^{[1
]}

Aishwarya, Richa ^{[2
]}

Miriyala, Sumitra ^{[3
]}

Bhuiyan, Mohammad Alfrad Nobel ^{[4
]}

Panchatcharam, Manikandan ^{[3
]}

Pattillo, Christopher B. ^{[2
]}

Orr, A. Wayne ^{[1
,2
,3
]}

Sadoshima, Junichi ^{[5
]}

Hill, Joseph A. ^{[6
,7
]}

Bhuiyan, Md. Shenuarin ^{[1
,2
]}

机构：

[1] Louisiana State Univ, Hlth Sci Ctr, Dept Pathol & Translat Pathobiol, Shreveport, LA 71103 USA

[2] Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71103 USA

[3] Louisiana State Univ, Hlth Sci Ctr, Dept Cellular Biol & Anat, Shreveport, LA 71103 USA

[4] Cincinnati Childrens Hosp, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA

[5] Rutgers New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA

[6] UT Southwestern Med Ctr, Dept Internal Med Cardiol, Dallas, TX 75390 USA

[7] UT Southwestern Med Ctr, Dept Mol Biol, Dallas, TX 75390 USA

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

基金：

美国国家卫生研究院;

关键词：

MAMMALIAN AUTOPHAGY; MOUSE HEARTS; CARDIOTOXICITY; DYSFUNCTION; DISRUPTION; DYNAMICS; BECLIN-1; NECROSIS; BINDING; PROTEIN;

D O I：

10.1038/s41598-018-37862-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Doxorubicin (Dox) is a highly effective anticancer drug but cause acute ventricular dysfunction, and also induce late-onset cardiomyopathy and heart failure. Despite extensive studies, the pathogenic sequelae leading to the progression of Dox-associated cardiomyopathy remains unknown. We assessed temporal changes in autophagy, mitochondrial dynamics, and bioenergetics in mouse models of acute and chronic Dox-cardiomyopathy. Time course study of acute Dox-treatment showed accumulation of LC3B II in heart lysates. Autophagy flux assays confirmed that the Dox-induced accumulation of autophagosomes occurs due to blockage of the lysosomal degradation process. Dox-induced autophagosomes and autolysosome accumulation were confirmed in vivo by using GFP-LC3 and mRFP-GFP-LC3 transgenic (Tg) mice. Mitochondria isolated from acute Dox-treated hearts showed significant suppression of oxygen consumption rate (OCR). Chronic Dox-cardiotoxicity also exhibited time-dependent accumulation of LC3B II levels and increased accumulation of green puncta in GFP-LC3 Tg hearts. Mitochondria isolated from chronic Dox-treated hearts also showed significant suppression of mitochondrial OCR. The in vivo impairment of autophagic degradation process and mitochondrial dysfunction data were confirmed in vitro using cultured neonatal cardiomyocytes. Both acute and chronic Dox-associated cardiomyopathy involves a multifocal disease process resulting from autophagosomes and autolysosomes accumulation, altered expression of mitochondrial dynamics and oxidative phosphorylation regulatory proteins, and mitochondrial respiratory dysfunction.

引用

页数：20

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