Activation of Insulin-Like Growth Factor II Receptor Induces Mitochondrial-Dependent Apoptosis through Gαq and Downstream Calcineurin Signaling in Myocardial Cells
Activation of Insulin-Like Growth Factor II Receptor Induces Mitochondrial-Dependent Apoptosis through Gαq and Downstream Calcineurin Signaling in Myocardial Cells
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DOI：
10.1210/en.2008-0975
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发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Huang, Chih-Yang
中科院分区：
文献类型：
--
作者：
Chu, Chun-Hsien;Tzang, Bor-Show;Huang, Chih-Yang
在以前的研究中，我们发现IGF-II和IGF-II受体（IGF-IIR）与腹主动脉完全结扎后病理性肥大的进展呈剂量依赖性相关，这可能在血管紧张素II诱导的心肌细胞凋亡中起关键作用。然而，IGF-IIR在响应IGF-II的细胞凋亡的调节中的详细机制仍不清楚。通过使用IGF-IR短发夹RNA抑制IGF-IR表达和使用Leu 27 IGF-II类似物特异性激活IGF-IIR，我们研究了IGF-II/IGF-IIR激活及其下游信号传导的作用。我们的研究结果表明，IGF-II协同增加细胞凋亡所诱导的抑制IGF-IR在新生大鼠心室肌细胞。Leu 27 IGF-II与IGF-IIR结合后，IGF-IIR与α-q多肽结合，作为蛋白偶联受体激活钙调磷酸酶，导致Bad易位到线粒体，细胞色素c释放到细胞质，导致心肌细胞凋亡。此外，通过RNA干扰抑制IGF-IIR、alpha-q多肽或钙调神经磷酸酶可阻断Leu 27 IGF-II诱导的细胞凋亡。总之，这项研究为IGF-IIR及其下游信号在心肌细胞凋亡中的作用提供了新的见解。抑制IGF-IIR信号通路可能是一个很好的策略，既保护心肌细胞凋亡和预防心力衰竭的进展。（内分泌学150：2723-2731，2009）
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)