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


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.





Published Version (Please cite this version)


Publication Info

Suliman, Hagir B, Martha Sue Carraway, Abdelwahid S Ali, Chrystal M Reynolds, Karen E Welty-Wolf and Claude A Piantadosi (2007). The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J Clin Invest, 117(12). pp. 3730–3741. 10.1172/JCI32967 Retrieved from

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.



Hagir B. Suliman

Associate Professor in Anesthesiology

Dr. Suliman is an expert in the molecular and cell biology of mammalian diseases, particularly in the molecular regulation of oxidant inflammatory responses in the heart and lung. She has a strong interest and expertise in the transcriptional control of cell metabolism, especially mitochondrial biogenesis and mitochondrial-mediated apoptosis and necrosis. Her recent publications have focused on the redox-regulation of nuclear transcription factors involved in both mitochondrial biogenesis and cellular adaptation to oxidative and nitrosative stress. Specifically, she has undertaken promoter analyses of nuclear respiratory factors-1 and -2 that indicate that these transcription factor genes are controlled by redox-regulated signaling networks activated by reactive oxygen and nitrogen species, and carbon monoxide. Dr. Suliman and her colleagues have reported that the cancer chemotherapeutic, doxorubicin, disrupts cardiac mitochondrial biogenesis through mitochondrial oxidant production, which promotes intrinsic apoptosis, while heme oxygenase-1 up-regulates adaptive mitochondrial biogenesis and opposes apoptosis through close regulation of mitochondrial ROS signaling by physiological CO production, thus forestalling fibrosis and cardiomyopathy. Most recently I have been defining the role of mitochondrial transcription factors in regulating cell survival, proliferation and differentiation including in embryonic stem cells and pluripotent cells.


Karen Elizabeth Welty-Wolf

Professor of Medicine

Dr. Welty-Wolf studies (1) pathophysiology and treatment of acute lung injury and (2) multiple organ failure and disordered energy metabolism in sepsis. Injury models include hyperoxic lung injury and ARDS with multiple organ failure due to sepsis. In addition to evaluating mechanisms of lung injury in sepsis, current studies are being conducted to evaluate the potential role of monoclinal antibodies to neutrophil adhesion molecules in the prevention of this injury. Other sepsis work includes evaluating mechanisms of oxidative damage to mitochondria. Additional research efforts include evaluating the use of human recombinant manganese superoxide dismutase in preventing hyperoxic lung injury.

Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.