Journal article
G-protein inactivator RGS6 mediates myocardial cell apoptosis and cardiomyopathy caused by doxorubicin
Cancer research (Chicago, Ill.), Vol.73(6), pp.1662-1667
03/15/2013
DOI: 10.1158/0008-5472.CAN-12-3453
PMCID: PMC3602152
PMID: 23338613
Abstract
Clinical use of the widely used chemotherapeutic agent doxorubicin is limited by life-threatening cardiotoxicity. The mechanisms underlying doxorubicin-induced cardiomyopathy and heart failure remain unclear but are thought to involve p53-mediated myocardial cell apoptosis. The tripartite G-protein inactivating protein RGS6 has been implicated in reactive oxygen species (ROS) generation, ATM/p53 activation, and apoptosis in doxorubicin-treated cells. Thus, we hypothesized that RGS6, the expression of which is enriched in cardiac tissue, might also be responsible for the pathologic effects of doxorubicin treatment in heart. In this study, we show that RGS6 expression is induced strongly by doxorubicin in the ventricles of mice and isolated ventricular myocytes via a posttranscriptional mechanism. While doxorubicin-treated wild-type (WT) mice manifested severe left ventricular dysfunction, loss of heart and body mass, along with decreased survival 5 days after doxorubicin administration, mice lacking RGS6 were completely protected against these pathogenic responses. Activation of ATM/p53 apoptosis signaling by doxorubicin in ventricles of WT mice was also absent in their RGS6(-/-) counterparts. Doxorubicin-induced ROS generation was dramatically impaired in both the ventricles and ventricular myocytes isolated from RGS6(-/-) mice, and the apoptotic response to doxorubicin in ventricular myocytes required RGS6-dependent ROS production. These results identify RGS6 as an essential mediator of the pathogenic responses to doxorubicin in heart, and they argue that RGS6 inhibition offers a rational means to circumvent doxorubicin cardiotoxicity in human patients with cancer.
Details
- Title: Subtitle
- G-protein inactivator RGS6 mediates myocardial cell apoptosis and cardiomyopathy caused by doxorubicin
- Creators
- Jianqi Yang - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USABiswanath MaityJie HuangZhan GaoAdele StewartRobert M WeissMark E AndersonRory A Fisher
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.73(6), pp.1662-1667
- DOI
- 10.1158/0008-5472.CAN-12-3453
- PMID
- 23338613
- PMCID
- PMC3602152
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- United States
- Grant note
- HL079031 / NHLBI NIH HHS R01 HL113001 / NHLBI NIH HHS HL70250 / NHLBI NIH HHS CA161882 / NCI NIH HHS R01 HL079031 / NHLBI NIH HHS R01 HL070250 / NHLBI NIH HHS HL62494 / NHLBI NIH HHS HL113001 / NHLBI NIH HHS R01 CA161882 / NCI NIH HHS R01 HL062494 / NHLBI NIH HHS
- Language
- English
- Date published
- 03/15/2013
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040336002771
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