Reactive Oxygen Species Derived from the NOX1 Isoform of NADPH Oxidase Exacerbate Doxorubicin-Induced Cardiotoxicity by Promoting Cardiac Remodeling

The anthracycline antitumor agent, doxorubicin (DOX) is known to cause dose-dependent cardiotoxicity. Involvement of NADPH oxidase in DOX-induced cardiotoxicity has been suggested in recent studies, but the exact molecular mechanism remains undefined. Administration of DOX to wild-type mice elicited marked up-regulation of a non-phagocytic isoform of NADPH oxidase, NOX1 in the heart, with a concomitant increase in reactive oxygen species (ROS). Dox-induced cardiac dysfunction and expression of pro-inflammatory cytokines were significantly suppressed in mice deficient in Nox1 (Nox1-KO). Histological analyses demonstrated that the development of cardiac fibrosis, accompanied by increased hydroxyproline content and activation of MMP-9, was significantly attenuated in Nox1-KO. These findings suggest that increased ROS production by NOX1/NADPH oxidase in the heart is among the exacerbation factors to promote inflammatory gene expression, cardiac dysfunction and remodeling in DOX treatment.