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

• Published in: Endocrinology (Philadelphia) 2009-06, Vol.150 (6), p.2723-2731
• Main Authors: Chu, Chun-Hsien, Tzang, Bor-Show, Chen, Li-Mien, Liu, Chung-Jung, Tsai, Fuu-Jen, Tsai, Chang-Hai, Lin, James A, Kuo, Wei-Wen, Bau, Da-Tian, Yao, Chun-Hsu, Huang, Chih-Yang
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin II; Aorta; Apoptosis; Biological and medical sciences; Calcineurin; Cardiac muscle; Cardiomyocytes; Cell activation; Congestive heart failure; Cytochrome c; Cytoplasm; Fundamental and applied biological sciences. Psychology; Gene expression; Growth factors; Hypertrophy; Insulin-like growth factor I receptors; Insulin-like growth factor II; Insulin-like growth factors; Mitochondria; Myocytes; Neonates; Polypeptides; Protein transport; Receptors; RNA-mediated interference; Translocation; Ventricle; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-0975

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 α-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, α-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. Findings provide a role of IGF-II in the cardiac cells via activating IGF-IIR signaling cascade, promoting mitochondrial-dependent apoptosis through Gαq and downstream calcineurin.