Atypical G Protein β5 Promotes Cardiac Oxidative Stress, Apoptosis, and Fibrotic Remodeling in Response to Multiple Cancer Chemotherapeutics.
Sreemoyee Chakraborti,Arnab Pramanick,Sudipta Saha,Somnath Singha Roy,Arnab Ray Chaudhuri,Madhusudan Das,Sujoy Ghosh,Adele Stewart,Biswanath Maity,Biswanath Maity +9 more
Reads0
Chats0
TLDR
The experiments suggest that inhibition of Gβ5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.Abstract:
The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. 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 proinflammatory and profibrotic 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 proapoptotic signaling cascades. In addition, Gβ5 loss allowed for maintenance of Δψm, basal mitochondrial calcium uniporter expression, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation-contraction coupling. The deleterious effects of Gβ5 are not restricted to VCM, however, as Gβ5 knockdown also reduces chemotherapy-induced release of proinflammatory cytokines (e.g., TNFα), hypertrophic factors (e.g., ANP), and profibrotic factors (e.g., TGFβ1) from both VCM and ventricular cardiac fibroblasts, with the most dramatic reduction occurring in cocultured cells. Our experiments suggest that Gβ5 facilitates the myofibroblast transition, the persistence of which contributes to pathologic 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. Indeed, intracardiac injection of Gβ5-targeted shRNA allowed for heart-specific protection against the damaging impact of chronic chemotherapy. Together, our results suggest that inhibition of Gβ5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.Significance: These findings suggest that inhibiting an atypical G-protein might provide a strategy to limit the cardiotoxicity in cancer patients treated with anthracyclines, taxanes, or fluoropyrimidines. Cancer Res; 78(2); 528-41. ©2017 AACR.read more
Citations
More filters
Journal ArticleDOI
The role of the mitochondrial calcium uniporter (MCU) complex in cancer.
TL;DR: Current knowledge on the role of the mitochondrial calcium uniporter (MCU) complex in multiple cancer types and models is reviewed and a perspective for future research and clinical considerations is provided.
Journal ArticleDOI
Melatonin attenuates doxorubicin-induced cardiotoxicity through preservation of YAP expression
TL;DR: It is suggested that melatonin treatment attenuated doxorubicin‐induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.
Journal ArticleDOI
Molecules and Mechanisms to Overcome Oxidative Stress Inducing Cardiovascular Disease in Cancer Patients.
Francesco Sabbatino,Valeria Conti,Luigi Liguori,Giovanna Polcaro,Graziamaria Corbi,Valentina Manzo,Vincenzo Tortora,Chiara Carlomagno,Carmine Vecchione,Amelia Filippelli,Stefano Pepe +10 more
TL;DR: In this paper, the role of ROS mediated oxidative stress mediated by oncological treatments in inducing cardiovascular disease was discussed and strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease.
Journal ArticleDOI
Polydatin protects against acute myocardial infarction-induced cardiac damage by activation of Nrf2/HO-1 signaling
TL;DR: In conclusion, polydatin effectively inhibited hypoxia- and AMI-induced myocardial damage by promotion of Nrf2/HO-1 signaling.
Journal ArticleDOI
Qiliqiangxin improves cardiac function and attenuates cardiac remodelling in doxorubicin-induced heart failure rats.
TL;DR: The beneficial effects of QL on DOX-induced CHF in rats are mediated by reduction in myocardial fibrosis, promotion of TGF-β3/Smad7, and inhibition of T GF-β1/ Smad3, which may also modulate specific miRNAs.
References
More filters
Journal ArticleDOI
Nox2 NADPH Oxidase Promotes Pathologic Cardiac Remodeling Associated with Doxorubicin Chemotherapy
Youyou Zhao,Declan McLaughlin,Emma Robinson,Adam Harvey,Michelle B. Hookham,Ajay M. Shah,Barbara McDermott,David J. Grieve +7 more
TL;DR: It is found that adverse effects of doxorubicin were attenuated by acute or chronic treatment with the AT1 receptor antagonist losartan, which is commonly used to reduce blood pressure.
Journal ArticleDOI
A growth factor for cardiac myocytes is produced by cardiac nonmyocytes.
TL;DR: A nonmyocyte-derived heparin-binding growth factor, tentatively named NMDGF, may represent a novel paracrine growth mechanism in myocardium.
Journal ArticleDOI
Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity
TL;DR: Doxorubicin-induced cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway, and is attenuated by pitavastatin through its antioxidant effect involving Rac1 inhibition.
Journal ArticleDOI
Complexes of the G Protein Subunit Gβ5 with the Regulators of G Protein Signaling RGS7 and RGS9 CHARACTERIZATION IN NATIVE TISSUES AND IN TRANSFECTED CELLS
Witherow Ds,Qiang Wang,Konstantin Levay,Jorge Cabrera,Jiandong Chen,Willars Gb,Vladlen Z. Slepak +6 more
TL;DR: Analysis of native G beta(5)-RGS and their coupled expression argue that in vivo, Gbeta(5) and Ggamma-like domain-containing RGSs only exist as heterodimers.
Journal ArticleDOI
Pifithrin-α protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice
TL;DR: The present experiments were designed to evaluate the effects of pifithrin-α (PFT-α), which is a p53 inhibitor, on doxorubicin (DOX)-induced apoptosis and cardiac injury.