Doxorubicin Inactivates Myocardial Cytochrome c Oxidase in Rats: Cardioprotection by Mito-Q

Abstract

Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown. The goals were to investigate the molecular mechanism of DOX-induced cardiomyopathy and cardioprotection by mitoquinone (Mito-Q), a triphenylphosphonium-conjugated analog of coenzyme Q, using a rat model. Rats were treated with DOX, Mito-Q, and DOX plus Mito-Q for 12 weeks. The left ventricular function as measured by two-dimensional echocardiography decreased in DOX-treated rats but was preserved during Mito-Q plus DOX treatment. Using low-temperature ex vivo electron paramagnetic resonance (EPR), a time-dependent decrease in heme signal was detected in heart tissues isolated from rats administered with a cumulative dose of DOX. DOX attenuated the EPR signals characteristic of the exchange interaction between cytochrome c oxidase (CcO)-Fe(III) heme a3 and CuB. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly downregulated the stable expression of the CcO subunits II and Va and had a slight inhibitory effect on CcO subunit I gene expression. Mito-Q restored CcO subunit II and Va expressions in DOX-treated rats. These results suggest a novel cardioprotection mechanism by Mito-Q during DOX-induced cardiomyopathy involving CcO.

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

“…DOX also decreased myocardial mitochondrial complex I and II activities, as well as the activity of the glutathione peroxidase (GPX). This is consistent with studies suggesting a key role for mitochondrial dysfunction and reactive oxygen species generation in triggering the deleterious cascade of the DOX-induced cardiotoxicity (4,5,28,29). In addition to mitochondrial, NADPH oxidase-dependent ROS generation (particularly NOX2-dependent) also may contribute to DOX-induced cardiotoxicity (4,30).…”

Acute adriamycin-induced cardiotoxicity is exacerbated by angiotension II

“…Singal et al (1997) demonstrated that both increasing oxidant and decreasing antioxidant play a key role in ADR-induced cardiotoxicity. Antioxidant enzymes such as catalase (Chandran et al 2009) and rapidly inactivated GPx1 (Simmons and Jamall 1989) have been reported to be less expressed or have lower activity in cardiac tissue. Therefore, cardiac tissue is very vulnerable for oxidative stress damage.…”

Ca2+entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance

“…To extend the potential translational implications of Trpm2 protection of the heart, we used a second model of cardiac injury: doxorubicin-induced cardiomyopathy (16), a model that involves oxygen free radicals (37) via Doxo's effects on mitochondrial electron transport chain (7,15). Survival of gKO mice treated with Doxo was much worse than WT mice treated similarly (Fig.…”