Enhancement of AG1024-Induced H9c2 Cardiomyoblast Cell Apoptosis via the Interaction of IGF2R with Gα Proteins and Its Downstream PKA and PLC-β Modulators by IGF-Ⅱ

Chu, Chun Hsien; Huang, Chih Yang; Lu, Ming; Lin, James A.; Tsai, Fuu Jen; Tsai, Chang Hai; Chu, Chia-Yih; Kuo, Wu Hsien; Chen, Li Mien; Chen, Ling Yun

doi:10.4077/cjp.2009.amh004

Cited by 13 publications

(15 citation statements)

References 27 publications

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“…The IGF‐2R has previously been linked to the Gi 2 (Nishimoto, 1993) and Gαq (Chu et al 2008) subunit signalling, where both were associated with cardiac hypertrophy (Böhm et al 1994; D’Angelo et al 1997). In an in vitro cardiomyocyte study of apoptosis, IGF‐2R activation resulted in decreased PKA protein expression (Chu et al 2009 a ), but no previous studies have shown a link between the IGF‐2R and cardiomyocyte hypertrophy involving Gαs signalling. Therefore our finding that IGF‐2R activation can cause cardiomyocyte hypertrophy in vivo , in a Gαs signalling‐dependent manner, is novel and this signalling could have potential implications for cardiac pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Activation of IGF‐2R stimulates cardiomyocyte hypertrophy in the late gestation sheep fetus

Wang¹,

Brooks²,

Thornburg³

et al. 2012

The Journal of Physiology

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Key points• This study investigates the impact that insulin-like growth factor 2 receptor (IGF-2R) activation has on the fetal heart, by infusing Leu 27 IGF-2 into the left circumflex coronary artery of the sheep fetus, to specifically activate IGF-2R and it's downstream signalling pathway.• Activation of cardiac IGF-2R resulted in cardiomyocyte hypertrophy, but with no changes in heart weight, cardiomyocyte proliferation, binucleation or apoptosis. This hypertrophy was mediated via protein kinase A activation.• Infusion of Leu 27 IGF-2 increases atrial natriuretic peptide abundance, a marker of cardiac pathological hypertrophy.• Cardiac IGF-2R activation may alter important regulators of cardiac contractility and relaxation by decreasing sarcoplasmic reticulum Ca 2+ -ATPase and phospho-troponin I abundance.• This study places the interaction between the IGF-2R and Gαs signalling pathway as a potential mechanism that can contribute to cardiomyocyte growth in fetal life, but which may result in pathological cardiac hypertrophy in postnatal life.Abstract In vitro studies using rat and fetal sheep cardiomyocytes indicate that, in addition to its role as a clearance receptor, the insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy. In the present study, we have determined the effect of specific activation of the IGF-2R in the heart of the late gestation fetus on cardiomyocyte development. Leu 27 IGF-2, an IGF-2R agonist, was infused into the fetal left circumflex coronary artery for 4 days beginning at 128.1 ± 0.4 days gestation. Ewes were humanely killed at 132.2 ± 1.2 days gestation (term, 150 days). Fetuses were delivered and hearts dissected to isolate the cardiomyocytes and to collect and snap-freeze tissue. Leu 27 IGF-2 infusion into the left circumflex coronary artery of fetal sheep increased the area of binucleated cardiomyocytes in the left, but not the right, ventricle. However, this infusion of Leu 27 IGF-2 did not change fetal weight, heart weight, blood pressure, blood gases or cardiomyocyte proliferation/binucleation. The increase in cardiomyocyte size in the Leu 27 IGF-2-infused group was associated with increased expression of proteins in the Gαs, but not the Gαq, signalling pathway. We concluded that infusion of Leu 27 IGF-2 into the left circumflex coronary artery causes cardiac IGF-2R activation in the left ventricle of the heart, and this stimulates cardiomyocyte hypertrophy in a Gαs-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Activation of IGF‐2R stimulates cardiomyocyte hypertrophy in the late gestation sheep fetus

Wang¹,

Brooks²,

Thornburg³

et al. 2012

The Journal of Physiology

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“…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). The upregulation of IGF-IIR gene expression occurred in this study after treatment with ANGII, LPS, inomycin, and TNF-a (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Chu

et al. 2011

Journal Cellular Physiology

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The IGF-II/mannose 6-phosphate receptor (IGF-IIR/Man-6-P) up-regulation correlates with heart disease progression and its signaling cascades directly trigger pathological cardiac hypertrophy, fibrosis, and cardiomyocytes apoptosis. IGF-IIR gene expression/ suppression is able to prevent myocardial remodeling. However, the regulating mechanisms for the IGF-IIR gene remain unclear. This study performed reverse transcriptase PCR (RT-PCR) and methylation-specific PCR (MS-PCR) to detect expression and DNA methylation of CpG islands within the IGF-IIR genomic DNA region. Our finding revealed that the IGF-IIR gene was up-regulated both in H9c2 cells treated with tumor necrosis factor-alpha (TNF-α), lipopolysaccharide (LPS), angiotensin II (ANGII) and inomycin, and age-dependently in spontaneously hypertensive rat (SHR) heart. For the DNA methylation study, although there were four CpG islands within IGF-IIR genomic regions, the DNA methylation distribution showed no change either in cells treated with ANGII or in the SHR heart. Using chemical inhibitors to individually block histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity, we found that histone acetylation was essential for ANGII-induced IGF-IIR gene expression using RT-PCR and luciferase assay. The Chromatin immuno-precipitation assay indicated that acetyl-Histone H3 and acetyl-Histone H4 associated with the IGF-IIR promoter increased in the presence of ANGII, otherwise methyl-CpG binding domain protein 2 (MeCP2) is disassociated with this. Taken together, this study demonstrates that histone acetylation plays a critical role in IGF-IIR up-regulation during pathological cardiac diseases and might provide a targeting gene in transcriptional therapies for the failing heart.

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“…Activation of IGF2R, a Gαq receptor, induces cardiac hypertrophy, through the activation of downstream effectors such as Ca 2+ –calmodulin‐dependent protein kinase II (CAMKII), protein kinase C (PKC)‐α and protein kinase A (PKA) (Chu et al . , ; Wang et al . ).…”

Section: Introductionmentioning

confidence: 99%

Maternal undernutrition in late gestation increases IGF2 signalling molecules and collagen deposition in the right ventricle of the fetal sheep heart

Darby

McMillen

Morrison

2018

The Journal of Physiology

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Exposure of the fetus to a range of environmental stressors, including maternal undernutrition, is associated with an increased risk of death from cardiovascular disease in adult life. This study aimed to determine the effect of maternal nutrient restriction in late gestation on the molecular mechanisms that regulate cardiac growth and development of the fetal heart. Maternal undernutrition resulted in a decrease in fetal glucose concentrations across late gestation, whilst fetal arterial PO2 remained unchanged between the control and late gestation undernutrition (LGUN) groups. There was evidence of an up-regulation of IGF2/IGF2R signalling through the CAMKII pathway in the fetal right ventricle in the LGUN group, suggesting an increase in hypertrophic signalling. LGUN also resulted in an increased mRNA expression of COL1A, TIMP1 and TIMP3 in the right ventricle of the fetal heart. In addition, there was an inverse relationship between fetal glucose concentrations and COL1A expression. The presence of interstitial fibrosis in the heart of the LGUN group was confirmed through the quantification of picrosirius red-stained sections of the right ventricle. We have therefore shown that maternal undernutrition in late gestation may drive the onset of myocardial remodelling in the fetal right ventricle and thus has negative implications for right ventricle function and cardiac health in later life.

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Enhancement of AG1024-Induced H9c2 Cardiomyoblast Cell Apoptosis via the Interaction of IGF2R with Gα Proteins and Its Downstream PKA and PLC-β Modulators by IGF-Ⅱ

Cited by 13 publications

References 27 publications

Activation of IGF‐2R stimulates cardiomyocyte hypertrophy in the late gestation sheep fetus

Activation of IGF‐2R stimulates cardiomyocyte hypertrophy in the late gestation sheep fetus

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

Maternal undernutrition in late gestation increases IGF2 signalling molecules and collagen deposition in the right ventricle of the fetal sheep heart

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