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Contribution of NADPH Oxidase (Nox)‐derived Reactive Oxygen Species (ROS) to Doxorubicin‐induced Cardiomyopathy Mediated by Regulator of G protein Signaling 6 (RGS6)

Oxidative stress, defined as an excess of reactive oxygen species (ROS) compared to antioxidant defenses, is implicated in the pathophysiology of heart failure. ROS play a critical role in regulation of cardiac myocyte apoptosis through control of redox‐sensitive signaling cascades and can also activate hypertrophic kinases, transcription factors and proteins involved in extracellular matrix remodeling. Nox proteins have emerged as major sources of ROS in the pathogenesis of myopathic changes associated with heart failure. RGS6 is a member of the RGS protein family of heterotrimeric G protein regulators. Our recent studies have identified an entirely novel signaling action of RGS6 as an upstream modulator of ROS‐dependent apoptosis in the heart. Mice lacking RGS6 are almost completely protected from ventricular ROS generation, cardiac myocyte apoptosis and loss of ventricular function in response to doxorubicin (Dox). We hypothesized that RGS6 is required for Nox‐dependent ROS production in cardiac myocytes induced by Dox and that it promotes apoptosis by a Nox‐ROS‐dependent mechanism. Nox2 and Nox4 are the major isoforms expressed in heart and are found in distinct subcellular locations. Plasma membrane bound Nox2 is critical for cardiac remodeling and contractile dysfunction in response to Dox. Here, we show increased Nox activity and a trend for increases in Nox 2 and Nox4 mRNA in hearts of wild type (WT) mice 5 days following Dox administration, as reported previously. These responses to Dox were not observed in mice lacking RGS6 suggesting that RGS6 is required for Dox‐induced Nox activation and possibly for increases in Nox mRNA expression in heart. In light of these findings, we examined the effects of Dox on cell death, caspase 3 activity and Nox activity in adult cardiomyocytes derived from WT, RGS6−/−, p47−/− (Nox2 subunit) and RGS6−/−; p47−/− double knockout mice. Individual loss of RGS6 or p47 blocked Dox‐induced increases in cell death, caspase 3 activity and Nox activity while their combined loss had no effect. These results provide new evidence that RGS6 is a critical upstream modulator of Nox‐derived ROS contributing to Dox‐induced cardiomyopathy. The mechanism(s) by which RGS6 modulates Nox activity in heart and the importance of the RGS6‐Nox‐ROS signaling cascade in oxidative stress‐induced cardiomyopathies are currently under investigation.