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

作者：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^*

来源：Endocrinology, 2009, 150(6): 2723-2731.

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 alpha-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, alpha-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. (Endocrinology 150: 2723-2731, 2009)

• 出版日期2009-6
• 单位中国医科大学