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Activation of Insulin-Like Growth Factor II Receptor Induces Mitochondrial-Dependent Apoptosis through Gq and Downstream Calcineurin Signaling in Myocardial Cells

Institute of Biochemistry and Biotechnology (C.-H.C., B.-S.T.), Chung Shan Medical University, Taichung 402, Taiwan; Department of Internal Medicine (L.-M.C.), Armed Force Taichung General Hospital, Taichung 411, Taiwan; Center of General Education (L.-M.C.), Central Taiwan University of Science and Technology, Taichung 40601, Taiwan; Graduate Institute of Chinese Medical Science (C.-J.L., F.-J.T., D.-T.B., C.-H.Y., C.-Y.H.), Departments of Pediatrics, Medical Research and Medical Genetics (F.-J.T.) and Department of Biomedical Imaging and Radiological Science (W.-W.K., C.-Y.H.), and Institute of Basic Medical Science (J.A.L., C.-Y.H.), China Medical University, Taichung 404, Taiwan; and Departments of Healthcare Administration (C.-H.T.) and Health and Nutrition Biotechnology (C.-Y.H.), Asia University, Taichung 41354, Taiwan

Address all correspondence and requests for reprints to: Chih-Yang Huang, Ph.D., Graduate Institute of Chinese Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan. E-mail: cyhuang{at}mail.cmu.edu.tw.

In previous studies, we have found that IGF-II and IGF-II receptor (IGF-IIR) dose dependently correlated with the progression of pathological hypertrophy after complete abdominal aorta ligation, which may play a critical role in angiotensin II-induced cardiomyocyte apoptosis. However, the detail mechanisms of IGF-IIR in the regulation of cell apoptosis in response to IGF-II remain unclear. By using IGF-IR short hairpin RNA to inhibit IGF-IR expression and using Leu27 IGF-II analog to activate specifically the IGF-IIR, we investigated the role of IGF-II/IGF-IIR activation and its downstream signaling. Our results revealed that IGF-II synergistically increased the cell apoptosis induced by suppressing of IGF-IR in neonatal rat ventricular myocytes. After binding of Leu27IGF-II, IGF-IIR became associated with -q polypeptide, acted like a protein-coupled receptor to activate calcineurin, led to the translocation of Bad into mitochondria and release of cytochrome c into cytoplasm, and contributed to mitochondrial-dependent apoptosis in neonatal rat ventricular myocytes. Furthermore, inhibition of IGF-IIR, -q polypeptide, or calcineurin by RNA interference could block the Leu27IGF-II-induced cell apoptosis. Together, this study provides a new insight into the effects of the IGF-IIR and its downstream signaling in myocardial apoptosis. Suppression of IGF-IIR signaling pathways may be a good strategy for both the protection against myocardial cell apoptosis and the prevention of heart failure progression.