Premium
: Atypical G protein β5 promotes cardiac oxidative stress and fibrotic remodeling in response to multiple cancer chemotherapeutics
Author(s) -
Chakraborti Sreemoyee,
Pramanick Arnab,
Maity Biswanath
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.661.2
Subject(s) - cardiotoxicity , oxidative stress , doxorubicin , myofibroblast , cancer research , myocyte , apoptosis , biology , medicine , fibrosis , pharmacology , microbiology and biotechnology , endocrinology , chemotherapy , biochemistry
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 Gβ 5 in the myocardium correlating with oxidative stress, myocyte apoptosis, and the accumulation of pro‐inflammatory and pro‐fibrotic cytokines. In ventricular cardiac myocytes (VCM) Gβ 5 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, Gβ 5 loss allowed for maintenance of Δψ m, basal MCU and mitochondrial Ca 2+ levels, effects likely to preserve functional myocyte excitation‐contraction coupling. The deleterious effects of Gβ 5 are not restricted to VCM, however, as Gβ 5 knockdown also reduces 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 VCF with the most dramatic reduction occurring in co‐cultured cells. Our experiments suggest that Gβ 5 facilitates the myofibroblast transition, the persistence of which contributes to pathological remodeling and heart failure. The convergence of Gβ 5 ‐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 Gβ 5 ‐targeted shRNA allowed for heart specific protection against the damaging impact of chronic chemotherapy. Together, our results suggest that inhibition of Gβ 5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes or fluoropyrimidines. Support or Funding Information Ramalingaswami Fellowship (BT/RLF/Re‐entry/15/2013), Department of Biotechnology, and Department of Science and Technology, SERB (EMR/2016/006873), Government of India to Dr. B Maity. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .