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Ventricular Nonmyocytes Inhibit Doxorubicin-Induced Myocyte Apoptosis: Involvement of Endogenous Endothelin-1 as a Paracrine Factor

Research Institute (T.T., H.O., J.H., K.M., S.S., K.K.) and Department of Medicine (T.H., F.Y., Y.K.), National Cardiovascular Center, Osaka 565-8565, Japan; and Department of Integrated Medicine (M.F.) and Second Department of Internal Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan

Address all correspondence and requests for reprints to: Takeshi Horio, M.D., Division of Hypertension and Nephrology, Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail: thorio{at}ri.ncvc.go.jp.

A cross-talk between cardiac myocytes and nonmyocytes via humoral factors plays an important role in the development of cardiac growth. However, it remains to be elucidated whether humoral factors produced from nonmyocytes have a protective effect on acute myocardial injury. The present in vitro study investigated the antiapoptotic effect of nonmyocytes on doxorubicin (DOX)-induced myocyte apoptosis and its molecular mechanism. Myocyte-nonmyocyte coculture and treatment with nonmyocyte-conditioned media significantly attenuated DOX-induced myocyte apoptosis. Treatment with nonmyocyte-conditioned media stimulated the phosphorylation of ERK, Akt, and cAMP response element-binding protein (CREB) in myocytes. Nonmyocyte-conditioned media also increased protein levels of Bcl-2 but not Bcl-xL and decreased caspase-3 activation induced by DOX. MAPK kinase-specific inhibitor PD98059, phosphatidylinositol-3 kinase-Akt inhibitor LY294002, and CREB antisense oligonucleotide significantly blocked the antiapoptotic effect of nonmyocyte-conditioned media. A considerable amount of endothelin (ET)-1 production was detected in nonmyocytes but not in myocytes. Exogenous ET-1 mimicked nonmyocyte-conditioned media-mediated ERK and CREB phosphorylation and Bcl-2 protein increase but not Akt phosphorylation. In addition, ET-A receptor antagonists BQ123 and BQ485 partially blocked nonmyocyte-conditioned media-mediated antiapoptotic effect, ERK and CREB phosphorylation, and Bcl-2 protein increase. Nonmyocyte-conditioned media and exogenous ET-1 unchanged protein levels of manganese superoxide dismutase and oxidative stress-related product levels augmented by DOX. The present findings demonstrate that cardiac nonmyocytes inhibit DOX-induced myocyte apoptosis, at least in part, via ET-1 secretion-mediated CREB activation independent of the decrease in oxidative stress.

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