Atypical G protein {beta}5 promotes cardiac oxidative stress, apoptosis, and fibrotic remodeling in response to multiple cancer chemotherapeutics

The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. We report here that, though distinct in their mechanisms of action, doxorubicin, paclitaxel, and 5-FU all induce rapid and robust upregulation of atypical G protein Gβ5 in the myocardium, correlating with oxidative stress, myocyte apoptosis, and the accumulation of pro-inflammatory and pro-fibrotic cytokines. In ventricular cardiac myocytes (VCM), Gβ5 deficiency provided substantial protection against the cytotoxic actions of chemotherapeutics, including reductions in oxidative stress and simultaneous attenuation of ROS-dependent activation of the ATM and CaMKII pro-apoptotic signaling cascades. In addition, Gβ5 loss allowed for maintenance of Δψm, basal MCU, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation-contraction coupling. Gβ5 knockdown also reduced chemotherapy-induced release of pro-inflammatory cytokines (e.g. TNFα), hypertrophic factors (e.g. ANP), and pro-fibrotic factors (e.g. TGFβ1) from both VCM and ventricular cardiac fibroblasts (VCF), with the most dramatic reductions occurring in co-cultured cells. Intracardiac injection of Gβ5-targeted shRNA allowed for heart specific protection against the damaging impact of chronic chemotherapy. These data suggest that Gβ5 facilitates the myofibroblast transition, the persistence of which contributes to pathological remodeling and heart failure. The convergence of Gβ5-mediated, ROS-dependent signaling pathways in both cell types represents a critical etiological factor in the pathogenesis of chemotherapy-induced cardiotoxicity.

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