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(Circulation. 2001;103:555.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Glycoprotein 130 Regulates Cardiac Myocyte Survival in Doxorubicin-Induced Apoptosis Through Phosphatidylinositol 3-Kinase/Akt Phosphorylation and Bcl-xL/Caspase-3 Interaction
Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8-11, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-462).
From the Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan (S.N., H.O., E.T., K.K., Y.F., T.K., K.Y.-T.), and the Division of Cardiovascular Research, St Elizabeth’s Medical Center of Boston, Tufts University School of Medicine, Boston, Mass (Y.F., K.W.). The first 2 authors contributed equally to this work.
Correspondence to Keiko Yamauchi-Takihara, MD, PhD, Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. E-mail takihara{at}imed3.med.osaka-u.ac.jp
Background—We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown.
Methods and Results—We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation.
Conclusions—Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.
Key Words: doxorubicin • kinases • caspases • glycoproteins
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