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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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Figure 7

HO-1 protects against DOX-induced mtDNA damage and apoptosis.

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HO-1 protects against DOX-induced mtDNA damage and apoptosis.
(A) Wester...
(A) Western blots of HO-1 expression before and after CO or HH in control mouse hearts compared with tubulin. (B) Bar graph shows mtDNA copy number measured by real-time PCR relative to nuclear DNA in H9c2 cells before and after HO-1 gene transfer. HO-1 transfection decreased DOX-dependent mtDNA depletion. HO-1–transfected cells treated with the specific Akt inhibitor (Akt8) showed loss of mtDNA protection by HO-1. HO-1 gene transfer also protected H9c2 cells from DOX-induced apoptosis, as shown by western blot analysis with an antibody to both intact and cleaved caspase-3. In HO-1–transfected H9c2 cells preincubated with Akt8, caspase-3 cleavage reemerged (mean ± SEM, n = 3; *P < 0.05 versus untreated cells). (C) Effect of DOX on cellular ATP content and the rescue by HO-1 transfection. *P < 0.05 compared with control and both HO-1 transfection studies. (D) HO-1 silencing in H9c2 cells. Western blot analysis demonstrated loss of HO-1 expression at 24 and 48 hours after HO-1 siRNA. Control cells stimulated with hemin (50 μM) were the positive control. Cells pretreated with p38 MAPK inhibitor SB203580 (10 μM) did not show a change in HO-1 protein induction by hemin after an additional 6 hours. (E) mtDNA copy number measured by real-time PCR in H9c2 cells without or with HO-1 silencing. Control or siHO-1 transfected cells were preincubated for 24 hours with DOX alone, with DOX and hemin, or with DOX, hemin, and SB203580. The graphs are means ± SEM for n = 3 per group. *P < 0.05 compared with control; †P < 0.05 compared with DOX alone.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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