A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte- extrinsic mechanisms of chemotherapy-induced cardiotoxicity

Dose-limiting cardiotoxicity remains a major limitation in the clinical use of cancer chemotherapeutics. Here, we describe a role for Regulator of G protein Signaling 7 (RGS7) in chemotherapy-dependent heart damage, the demonstration for a functional role of RGS7 outside of the nervous system and retina. Though expressed at low levels basally, we observed robust up-regulation of RGS7 in the human and murine myocar-dium following chemotherapy exposure. In ventricular cardiomyocytes (VCM), RGS7 forms a complex with Ca2+/calmodulin-dependent protein kinase (CaMKII) supported by key residues (K412 and P391) in the RGS domain of RGS7. In VCM treated with chemotherapeutic drugs, RGS7 facilitates CaMKII oxidation and phosphorylation and CaMKII-dependent oxidative stress, mitochondrial dysfunction, and apoptosis. Cardiac-specific RGS7 knockdown protected the heart against chemotherapy -depend-ent oxidative stress, fibrosis, and myocyte loss and improved left ventricular function in mice treated with doxorubicin. Conversely, RGS7 overexpression induced fibrosis, reactive oxygen species generation, and cell death in the murine myocardium that were mitigated following CaMKII inhibition. RGS7 also drives production and release of the cardiokine neuregulin-1, which facilitates paracrine communication between VCM and neighboring vascular endothelial cells (EC), a maladaptive mechanism contrib-uting to VCM dysfunction in the failing heart. Importantly, while RGS7 was both necessary and sufficient to facilitate chemotherapy-dependent cytotoxicity in VCM, RGS7 is dispensable for the cancer-killing actions of these same drugs. These selective myocyte-intrinsic and myocyte-extrinsic actions of RGS7 in heart identify RGS7 as an attractive therapeutic target in the mitigation of chemotherapy-driven cardiotoxicity.SignificanceDespite decades of clinical use, the utility of cancer chemotherapeutics is limited by adverse cardiac events. Although progress has been made in elucidating mechanisms underlying the pathogenesis of chemotherapy-dependent cardiotoxicity, the highly diverse rate of disease progression and lack of biomarkers have stymied efforts to prevent or reverse cardiac damage. Here, we identify RGS7, up-regulated in cardiac cells following chemotherapy exposure, as a key driver of chemotherapy -dependent oxidative stress, cell loss, and fibrosis in heart. Importantly, while RGS7 is both necessary and sufficient to drive chemotherapy-dependent heart damage, modulation of RGS7 expression in cancer cells fails to impact their sensitivity to chemotherapeutic drugs. Thus, RGS7 emerges as a potential therapeutic target in the detection or mitigation of chemotherapy -associated cardiac damage.

Automated summary

This study identifies RGS7 as a key driver of chemotherapy-induced oxidative stress, cell loss, and fibrosis in the heart. Importantly, RGS7 does not impact the sensitivity of cancer cells to chemotherapeutic drugs. Therefore, RGS7 emerges as a potential therapeutic target for detecting or mitigating chemotherapy-associated cardiac damage.