TY - JOUR
T1 - Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration
AU - Abdullah, Chowdhury S.
AU - Alam, Shafiul
AU - Aishwarya, Richa
AU - Miriyala, Sumitra
AU - Bhuiyan, Mohammad Alfrad Nobel
AU - Panchatcharam, Manikandan
AU - Pattillo, Christopher B.
AU - Orr, A. Wayne
AU - Sadoshima, Junichi
AU - Hill, Joseph A.
AU - Bhuiyan, Md Shenuarin
N1 - Funding Information:
This work was supported by the National Institutes of Health National Institutes of Health grants: K99 HL122354 and R00 HL122354 to M. S. B.; LSUHSC-S Feist Weiller Cancer Center IDEA Grant to M.S.B.; R01 HL098435 and R01 HL133497 to A.W.O.; PGM121307A to M.S.B., A.W.O., M.P. and C.B.P.; NIH HL-120732; HL-128215; HL-126012 to J.A.H., American Heart Association 14SFRN20740000 to J.A.H., CPRIT RP110486P3 to J.A.H., and the Leducq Foundation 11CVD04 to J.A.H.; LSUHSC-S Malcolm Feist Cardiovascular Postdoctoral Fellowship to C.S.A.; AHA Postdoctoral Fellowship to S. A.; and LSUHSC-S Malcolm Feist Pre-doctoral Fellowship to R.A.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-018-37862-3
DO - 10.1038/s41598-018-37862-3
M3 - Article
C2 - 30765730
AN - SCOPUS:85061563251
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 2002
ER -