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

dc.contributor.author Ali, AS
dc.contributor.author Carraway, MS
dc.contributor.author Piantadosi, Claude Anthony
dc.contributor.author Reynolds, CM
dc.contributor.author Suliman, Hagir B
dc.contributor.author Welty-Wolf, KE
dc.coverage.spatial United States
dc.date.accessioned 2017-04-12T13:13:12Z
dc.date.issued 2007-12
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/18037988
dc.identifier.issn 0021-9738
dc.identifier.uri https://hdl.handle.net/10161/13989
dc.description.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.
dc.language eng
dc.relation.ispartof J Clin Invest
dc.relation.isversionof 10.1172/JCI32967
dc.subject 3-Phosphoinositide-Dependent Protein Kinases
dc.subject Animals
dc.subject Antibiotics, Antineoplastic
dc.subject Antimetabolites
dc.subject Apoptosis
dc.subject Carbon Monoxide
dc.subject Cardiomyopathies
dc.subject Caspase 3
dc.subject Cells, Cultured
dc.subject DNA, Mitochondrial
dc.subject Doxorubicin
dc.subject Fibrosis
dc.subject GATA4 Transcription Factor
dc.subject Gene Silencing
dc.subject Guanylate Cyclase
dc.subject Heme Oxygenase (Decyclizing)
dc.subject Male
dc.subject Mice
dc.subject Mitochondria, Heart
dc.subject Myocardium
dc.subject Necrosis
dc.subject Protein-Serine-Threonine Kinases
dc.subject Proto-Oncogene Proteins c-akt
dc.subject Rats
dc.subject Sarcomeres
dc.title The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy.
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/18037988
pubs.begin-page 3730
pubs.end-page 3741
pubs.issue 12
pubs.organisational-group Anesthesiology
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Pulmonary, Allergy, and Critical Care Medicine
pubs.organisational-group Pathology
pubs.organisational-group School of Medicine
pubs.publication-status Published
pubs.volume 117


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