Activation of insulin-like growth factor II receptor induces mitochondrial-dependent apoptosis through G(alpha)q and downstream calcineurin signaling in myocardial cells.
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.
Chu
Chun-Hsien
CH
Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan.
Tzang
Bor-Show
BS
Chen
Li-Mien
LM
Liu
Chung-Jung
CJ
Tsai
Fuu-Jen
FJ
Tsai
Chang-Hai
CH
Lin
James A
JA
Kuo
Wei-Wen
WW
Bau
Da-Tian
DT
Yao
Chun-Hsu
CH
Huang
Chih-Yang
CY
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000502:physiology*; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494821:Bad protein, rat; D017527:Receptor, IGF Type 2; D051025:bcl-Associated Death Protein; D045304:Cytochromes c; D019703:Calcineurin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11