title: G-protein inactivator RGS6 mediates myocardial cell apoptosis and cardiomyopathy caused by doxorubicin.
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.
authors: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
authors: Jianqi
authors: J
authors: Yang
authors: Biswanath
authors: B
authors: Maity
authors: Jie
authors: J
authors: Huang
authors: Zhan
authors: Z
authors: Gao
authors: Adele
authors: A
authors: Stewart
authors: Robert M
authors: RM
authors: Weiss
authors: Mark E
authors: ME
authors: Anderson
authors: Rory A
authors: RA
authors: Fisher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D009202:Cardiomyopathies / Q000139:chemically induced*; D004317:Doxorubicin / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D020710:RGS Proteins / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D020710:RGS Proteins; C400194:RGS6 protein, human; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D019204:GTP-Binding Proteins