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    Please use this identifier to cite or link to this item: http://asiair.asia.edu.tw/ir/handle/310904400/16323

    Title: Activation of Insulin-Like Growth Factor II Receptor Induces Mitochondrial-Dependent Apoptosis through G q and Downstream Calcineurin Signaling in Myocardial Cells
    Authors: ;Chu, Chun-Hsien;Tzang, Bor-Show;Chen, Li-Ming;Liu, Chung-Jung;Tsai, Fuu-Jen;Tsai, Chang-Hai;James, A.Lin;Kuo, Wei-Wen;Bau, Da-Tian;Yao, Chun-Hsu;黃志揚;HUANG, CHIH-YANG
    Contributors: 生物科技學系
    Date: 2009-06
    Issue Date: 2012-11-23 17:11:29 (UTC+8)
    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 α-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, α-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.

    The IGF system comprises three ligands (IGF-I, IGF-II, and insulin), three receptors [IGF-I receptor (IGF-IR), IGF-II/mannose 6-phosphate receptor (IGF-IIR), and insulin receptor], and a variety of IGF binding proteins (IGFBPs) (1). Those ligands are able to bind with each of the three receptors with distinct affinity to perform distinct physiological function regulation. For instance, IGF-I has higher binding affinity to IGF-IR than those of IGF-II and insulin. Binding of IGFs to IGF-IR and insulin receptor triggers a series of intracellular signaling cascades that regulate cell growth, development, and metabolic effects, respectively (1, 2). In contrast, the IGF-IIR stabilizes local IGF concentration through internalization and lysosomal degradation, referred to as a “clearance receptor” (3). The putative G protein binding site of IGF-IIR reveals that IGF-II may regulate G protein-relative signaling pathways through IGF-IIR (4, 5), linking to a variety of physiological functions (6, 7, 8). However, the role of IGF-II/IGF-IIR and their downstream signaling in heart remain unclear.

    The knockout of the IGF-IIR gene in transgenic mice has been associated with overproliferation of myocardial cells in ventricular hyperplasia and impairs cardiac development (9). In patients with chronic heart failure, IGF-IIR has been suggested to up-regulate TGF-β by cleaving latent TGF-β (10, 11). Additional evidence has shown that IGF-IIR functions as a death receptor or a tumor suppressor gene involved in apoptosis and tumorigenesis (12). Moreover, the disruption of IGF-IIR protein mediated by ribozyme leads to cellular protection against cardiomyocyte apoptosis (13), implying that IGF-IIR may play a critical role in regulation of cell apoptosis, which might contribute to heart failure. However, the molecular mechanisms underlying IGF-IIR induction of cell apoptosis in the heart remain poorly understood.

    Apoptosis has been identified in a wide variety of cardiovascular disorders, including myocardial infarction and heart failure (14). In mammalian cells the apoptotic responses are mediated through either the intrinsic or extrinsic pathways, triggering the activation of caspase cascade (15). All the apoptotic molecules involved may contribute to cardiomyocyte loss and dysfunction. Like IGF-I, IGF-II is thought to be a potential candidate for heart failure treatment through activating the IGF-IR pathway due to promote physiological cardiac growth, improve heart contraction, and attenuate pathological hypertrophy, cell death, and fibrosis in a pressure overload model (2, 16). However, unexpected pathological stress-induced IGF-II and IGF-IIR in cardiomyocyte raised our interest in clarifying the mysterious role of IGF-II/IGF-IIR in protection against cardiomyocyte apoptosis (17, 18, 19). In our hypothesis we proposed that IGF-IIR activation might trigger its downstream cascades and promote the cardiomyocyte apoptosis corresponding to the progression of heart failure.

    First, to exclude the possible intervention of IGF-IR, IGF-IR short hairpin RNA (shRNA) was used to ensure that IGF-II could distinctly bind to IGF-IIR and activate intracellular signaling without the interference of IGF-IR. It was found that treatment with IGF-II synergistically increases the level of cell apoptosis in the suppression of IGF-IR in neonatal rat ventricular myocytes (NRVMs). Leu27IGF-II, an analog of IGF-II that interacts selectively with IGF-IIR (20), was then used to specifically trigger IGF-IIR signaling cascades. The results showed that Leu27IGF-II could induce the mitochondrial-dependent apoptosis by activating calcineurin in NRVMs, and the Leu27IGF-II-induced cell apoptosis and calcineurin activation were both reversed by IGF-IIR down-regulation. Furthermore, the Leu27IGF-II induction of calcineurin activity and cell apoptosis was needed for interaction of α-q polypeptide (Gαq) and IGF-IIR. The signaling cascade of triggering mitochondrial apoptosis in NRVMs is through binding of IGF-II with IGF-IIR, interacting of IGF-IIR with Gαq, and activating of calcineurin. Together, suppression of the IGF-IIR and its signaling may contribute both to the prevention of cardiomyocyte apoptosis found in certain heart diseases, and to the retardation of heart failure progression."
    Appears in Collections:[生物科技學系] 期刊論文

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