The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy.
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.
Type
Journal articleSubject
3-Phosphoinositide-Dependent Protein KinasesAnimals
Antibiotics, Antineoplastic
Antimetabolites
Apoptosis
Carbon Monoxide
Cardiomyopathies
Caspase 3
Cells, Cultured
DNA, Mitochondrial
Doxorubicin
Fibrosis
GATA4 Transcription Factor
Gene Silencing
Guanylate Cyclase
Heme Oxygenase (Decyclizing)
Male
Mice
Mitochondria, Heart
Myocardium
Necrosis
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
Rats
Sarcomeres
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https://hdl.handle.net/10161/13989Published Version (Please cite this version)
10.1172/JCI32967Publication Info
Suliman, Hagir B; Carraway, Martha Sue; Ali, Abdelwahid S; Reynolds, Chrystal M; Welty-Wolf,
Karen E; & Piantadosi, Claude A (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 https://hdl.handle.net/10161/13989.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.
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Show full item recordScholars@Duke
Claude Anthony Piantadosi
Professor Emeritus of Medicine
Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of
acute organ failure, particularly acute lung injury (ALI), with an emphasis on the
molecular regulatory roles of the physiological gases— oxygen, carbon monoxide,
and nitric oxide— as they relate to the damage responses to acute inflammation.
The basic science focuses on oxidative processes and redox-regulation, especially
the molecular mechanisms by which reactive oxygen and nitrogen species trans
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
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 inc
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