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

摘要: 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 upregulate nuclear program for biogenesis its associated intrinsic antiapoptosis proteins, leading severe DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, excessive wall stress fibrosis. Furthermore, exploited recent evidence regulated CO/heme oxygenase (CO/HO) system ameliorate doxorubicin in mice. We found myocardial pathology was averted periodic CO inhalation, which restored circumvented apoptosis through caspase-3 apoptosis-inducing factor. Moreover, simultaneously reversed doxorubicin-induced loss binding GATA-4 critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented mtDNA depletion via activation Akt1/PKB guanylate cyclase, while gene silencing exacerbated Thus disrupts biogenesis, promotes CO/HO opposes forestalling fibrosis cardiomyopathy. These findings imply therapeutic index cancer chemotherapeutics can be improved protection biogenesis.