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

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.

Alpinate Oxyphyllae Fructus (Alpinia Oxyphylla Miq) Extracts Inhibit Angiotensin-II Induced Cardiac Apoptosis in H9c2 Cardiomyoblast Cells

“…28) After Ang II stimulation, intracellular Ca 2þ accumulation alters mitochondrial membrane permeability, leading to a release of cytochrome c into the cytoplasm and subsequent apoptotic cascades in neonatal rat ventricular myocytes. 25) AOF is one of the most important traditional Chinese medicines, and is reported to be a neuro-protective agent. [29][30][31][32][33] It is used to treat patients with various symptoms accompanying hypertension and cerebrovascular disorders in Korea.…”

“…23) Insulin-like growth factor II (IGF-II) also contributes by stimulating neonatal rat ventricular myocyte or H9c2 cell hypertrophy, apoptosis and remodeling. [24][25][26][27] Our previous study found that Ang II appeared to evoke IGF-II and IGF-IIR through the ERK and the JNK signaling pathway respectively, and further to activate cardiac cell apoptosis via calcineurin dependent pathways, 28) ultimately causing heart failure.…”

Histone acetylation is essential for ANG‐II‐induced IGF‐IIR gene expression in H9c2 cardiomyoblast cells and pathologically hypertensive rat heart

“…According to its conventional role, IGF-IIR functions as a death receptor or a tumor suppression gene involved in the cytotoxic T cell-induced apoptosis and tumorigenesis (Motyka et al, 2000;Leboulleux et al, 2001). In the heart, the IGF-IIR disruption leads to cellular protection against cardiomyocyte apoptosis (Chen et al, 2004) and IGF-II and IGF-IIR up regulation in cardiomyocytes have been identified in a variety of heart disease models (Lee et al, 2006;Chang et al, 2008;Chu et al, 2008Chu et al, , 2009b. IGF-IIR could also function as a G proteincoupled receptor to trigger its downstream signaling modulators such as PKC-a/CaMKII, calcineurin and MMP/ TIMP, contributing to heart failure progression (Chang et al, 2008;Chu et al, 2008Chu et al, , 2009aChen et al, 2009).…”

Responses of muscle mass, strength and gene transcripts to long-term heat stress in healthy human subjects

“…There were several reports explaining that exercise training depressed transcription of TTN gene in mammalian skeletal muscles (Lehti et al 2007;Velders et al 2008), and these results might be consistent with our current study. On the other hand, the IGF2R-dependent signaling pathway was suspected to be involved in the induction of cell apoptosis in the myocardium (Chu et al 2009). Overall, the physiological significance(s) of the decrease in the transcription level of TTN and IGF2R genes is still unclear.…”