Premium
Regulator of G protein signaling 6 (RGS6) mediates doxorubicin‐induced myocardial cell apoptosis and cardiomyopathy
Author(s) -
Yang Jianqi,
Maity Biswanath,
Huang Jie,
Gao Zhan,
Stewart Adele,
Weiss Robert M,
Anderson Mark E,
Fisher Rory A
Publication year - 2013
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.27.1_supplement.1031.7
Subject(s) - apoptosis , reactive oxygen species , biology , cancer research , cardiomyopathy , microbiology and biotechnology , programmed cell death , doxorubicin , heart failure , chemistry , medicine , genetics , chemotherapy
Activation of p53 and myocardial apoptosis are crucial events responsible for Dox‐induced cardiomyopathy and heart failure. Recently we discovered a novel signaling role for RGS6 in mediating activation by Dox of the ATM/p53 apoptosis pathway via reactive oxygen species (ROS), which are also strongly implicated in myocardial apoptosis. Here, we investigated whether RGS6 was involved in the pathogenic response to Dox in heart. While Dox‐treated wild type (WT) mice manifested severe left ventricular dysfunction, loss of heart and body mass, and decreased survival five days following Dox administration, RGS6 −/− mice were completely protected against these pathogenic responses. The activation of ATM/p53‐apoptosis signaling by Dox in ventricles of WT mice was completely absent in their RGS6 −/− counterparts. Dox‐induced ROS generation was dramatically impaired in ventricles and isolated VCM from RGS6 −/− mice, and RGS6 was required for Dox‐induced apoptosis in VCM, which was also found to be ROS‐dependent. Thus, RGS6 is a previously unrecognized, but essential, mediator of the pathogenic responses to Dox in heart where RGS6 promotes activation of apoptotic signaling pathways by modulating Dox‐induced ROS generation. RGS6 inhibition might represent a viable means to circumvent the cardiotoxic actions of Dox in human cancer patients. (AHA 11SDG7580008 and NIH CA161882, HL079031, HL62494, HL70250 and HL113001)