Enhancement of AG1024-Induced H9c2 Cardiomyoblast Cell Apoptosis via the Interaction of IGF2R with Gα Proteins and Its Downstream PKA and PLC-β Modulators by IGF-Ⅱ

10.4077/CJP.2009.AMH004

Chun-Hsien Chu；Chih-Yang Huang；Ming-Chin Lu；James A. Lin；Fuu-Jen Tsai；Chang-Hai Tsai；Chia-Yih Chu；Wu-Hsien Kuo；Li-Mien Chen；Ling-Yun Chen

IGF-Ⅱ ； apoptosis ； Gα ； IGF2R

The Chinese Journal of Physiology

52卷1期（2009 / 02 / 01）

31 - 37

英文

Our previous studies found that insulin-like growth factor-I receptor (IGF1R) signaling blockade caused cardiac hypertrophy, and that apoptosis is required for upregulating the IGF-Ⅱ and the IGF-Ⅱ mannose 6-phosphate receptor (IGF2R) gene. However, the role of IGF-Ⅱ in the regulation of cell apoptosis through IGF2R is little known. In this study, we hypothesized that IGF-Ⅱ may induce cell apoptosis through IGF2R but is dependent on IGF1R activity. Western blots and TUNEL assay revealed that in the presence of IGF1R, exogenous IGF-Ⅱ acts, like IGF-Ⅰ, would increase phospho-Akt through IGF1R, but does not affect the caspase 3 activation and apoptotic induction in H9c2 cardiomyoblast cells. Conversely, AG1024, an inhibitor of IGF1R activity, causes cell apoptosis, and the treatment with IGF-Ⅱ further enhances this process, implying that it occurs through IGF2R. Moreover, immunoprecipitation assay revealed that treatment with IGF-Ⅱ could enhance the interaction of IGF2R with Gαi and Gαq but reduce its binding with Gαs, resulting in the reduction of phospho-PKA and the activation of PLC-β. Taken together, these data provide new insight into the dual role of IGF-Ⅱ in the control of IGF1R dependent cell apoptosis and involved activation of IGF2R signaling. Improving IGF1R activity and suppressing IGF2R may be a good strategy to prevent the progression of heart disease with cardiomyocyte apoptosis.

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