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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases
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Animals
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Antibiotics, Antineoplastic / adverse effects*
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Antibiotics, Antineoplastic / pharmacology
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Antimetabolites / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Carbon Monoxide / pharmacology*
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Cardiomyopathies / chemically induced
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Cardiomyopathies / enzymology*
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Cardiomyopathies / genetics
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Cardiomyopathies / pathology
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Caspase 3 / biosynthesis
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Caspase 3 / genetics
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Cells, Cultured
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DNA, Mitochondrial / genetics
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DNA, Mitochondrial / metabolism
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Doxorubicin / adverse effects*
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Doxorubicin / pharmacology
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Fibrosis
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GATA4 Transcription Factor / genetics
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GATA4 Transcription Factor / metabolism
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Gene Silencing
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Guanylate Cyclase / genetics
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Guanylate Cyclase / metabolism
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Heme Oxygenase (Decyclizing) / genetics
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Heme Oxygenase (Decyclizing) / metabolism*
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Male
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Mice
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Mitochondria, Heart / enzymology*
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Mitochondria, Heart / genetics
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Mitochondria, Heart / pathology
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Myocardium / enzymology
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Myocardium / pathology
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Necrosis / chemically induced
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Necrosis / enzymology
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Necrosis / genetics
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Necrosis / pathology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Sarcomeres / enzymology
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Sarcomeres / genetics
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Sarcomeres / pathology
Substances
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Antibiotics, Antineoplastic
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Antimetabolites
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DNA, Mitochondrial
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GATA4 Transcription Factor
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Carbon Monoxide
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Doxorubicin
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Heme Oxygenase (Decyclizing)
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Hmox1 protein, rat
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3-Phosphoinositide-Dependent Protein Kinases
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Akt1 protein, mouse
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Casp3 protein, mouse
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Caspase 3
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Guanylate Cyclase