Author(s): Chu, CH (Chu, Chun-Hsien); Tzang, BS (Tzang, Bor-Show); Chen, LM (Chen, Li- Mien); Liu, CJ (Liu, Chung-Jung); Tsai, FJ (Tsai, Fuu-Jen); Tsai, CH (Tsai, Chang-Hai); Lin, JA (Lin, James A.); Kuo, WW (Kuo, Wei-Wen); Bau, DT (Bau, Da-Tian); Yao, CH (Yao, Chun- Hsu); Huang, CY (Huang, Chih-Yang)
Title: Activation of Insulin-Like Growth Factor II Receptor Induces Mitochondrial-Dependent Apoptosis through G alpha q and Downstream Calcineurin Signaling in Myocardial Cells Source: ENDOCRINOLOGY, 150 (6): 2723-2731 JUN 2009
Language: English Document Type: Article
KeyWords Plus: MANNOSE 6-PHOSPHATE RECEPTOR; RAT CARDIAC MYOCYTES;
HEART-FAILURE; CARDIOMYOBLAST APOPTOSIS; G-PROTEINS; IGF-II; CALCIUM;
BINDING; STIMULATION; PATHWAY
Abstract: 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)
Addresses: [Chu, Chun-Hsien; Tzang, Bor-Show] Chung Shan Med Univ, Inst Biochem &
Biotechnol, Taichung 402, Taiwan; [Chen, Li-Mien] Armed Force Taichung Gen Hosp, Dept Internal Med, Taichung 411, Taiwan; [Chen, Li-Mien] Cent Taiwan Univ Sci & Technol, Ctr Gen Educ, Taichung 40601, Taiwan; [Tsai, Fuu-Jen] China Med Univ, Dept Pediat, Taichung 404, Taiwan; [Tsai, Fuu-Jen] China Med Univ, Dept Med Res & Med Genet, Taichung 404, Taiwan; [Kuo, Wei-Wen; Huang, Chih-Yang] China Med Univ, Dept Biomed Imaging & Radiol Sci, Taichung 404, Taiwan; [Lin, James A.; Huang, Chih-Yang] China Med Univ, Inst Basic
Med Sci, Taichung 404, Taiwan; [Tsai, Chang-Hai] Asia Univ, Dept Healthcare Adm, Taichung 41354, Taiwan; [Huang, Chih-Yang] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung 41354, Taiwan; [Liu, Chung-Jung; Tsai, Fuu-Jen; Bau, Da-Tian; Yao, Chun-Hsu; Huang, Chih-Yang]
China Med Univ, Grad Inst Chinese Med Sci, Taichung 404, Taiwan
Reprint Address: Huang, CY, China Med Univ, Grad Inst Chinese Med Sci, 91 Hsueh Shih Rd, Taichung 404, Taiwan.
E-mail Address: [email protected] Funding Acknowledgement:
Funding Agency Grant Number
National Science Council (NSC), Taiwan NSC 94-2320-B-040-017 NSC 96-2320-B-039-036
This study was supported by grants from the National Science Council (NSC), Taiwan (NSC 94-2320-B-040-017, NSC 96-2320-B-039-036).
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Publisher: ENDOCRINE SOC
Publisher Address: 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815- 5817 USA
ISSN: 0013-7227
DOI: 10.1210/en.2008-0975
29-char Source Abbrev.: ENDOCRINOLOGY ISO Source Abbrev.: Endocrinology
Source Item Page Count: 9
Subject Category: Endocrinology & Metabolism ISI Document Delivery No.: 448IQ
