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Citations to this article

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy
Hagir B. Suliman, … , Karen E. Welty-Wolf, Claude A. Piantadosi
Hagir B. Suliman, … , Karen E. Welty-Wolf, Claude A. Piantadosi
Published November 21, 2007
Citation Information: J Clin Invest. 2007;117(12):3730-3741. https://doi.org/10.1172/JCI32967.
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Research Article Cardiology Article has an altmetric score of 7

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

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Abstract

The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.

Authors

Hagir B. Suliman, Martha Sue Carraway, Abdelwahid S. Ali, Chrystal M. Reynolds, Karen E. Welty-Wolf, Claude A. Piantadosi

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 Total
Citations: 2 5 8 9 7 4 3 9 5 12 12 10 7 14 7 8 8 6 136
Citation information
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Citations to this article in year 2017 (5)

Title and authors Publication Year
Mitochondrial quality-control dysregulation in conditional HO-1-/- mice
Hagir Suliman, Jeffrey Keenan, Claude A Piantadosi
JCI Insight 2017
Protein Kinase A/CREB Signaling Prevents Adriamycin-Induced Podocyte Apoptosis via Upregulation of Mitochondrial Respiratory Chain Complexes
K Xie, M Zhu, P Xiang, X Chen, A Kasimumali, R Lu, Q Wang, S Mou, Z Ni, L Gu, H Pang
Molecular and cellular biology 2017
An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity
JY Beak, W Huang, JS Parker, ST Hicks, C Patterson, PC Simpson, A Ma, J Jin, BC Jensen
JACC: Basic to Translational Science 2017
Fibroblast growth factor-2-mediated protection of cardiomyocytes from the toxic effects of doxorubicin requires the mTOR/Nrf-2/HO-1 pathway
N Koleini, BE Nickel, J Wang, Z Roveimiab, RR Fandrich, LA Kirshenbaum, PA Cattini, E Kardami
Oncotarget 2017
Apoptosis and remodeling in adriamycin-induced cardiomyopathy rat model
YM Hong, H Lee, MS Cho, KC Kim
Korean Journal of Pediatrics 2017

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