Wang Kimberley C W, Tosh Darran N, Zhang Song, McMillen I Caroline, Duffield Jaime A, Brooks Doug A, Morrison Janna L
Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia; and.
Mechanisms in Cell Biology and Disease Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
Am J Physiol Regul Integr Comp Physiol. 2015 Apr 1;308(7):R627-35. doi: 10.1152/ajpregu.00346.2014. Epub 2015 Jan 28.
The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life.
心脏胰岛素样生长因子2受体（IGF-2R）可通过涉及αq（Gαq）或αs（Gαs）的异三聚体G蛋白受体偶联方式诱导心肌细胞肥大。我们之前已经表明，与平均出生体重（ABW）的羔羊相比，低出生体重（LBW）的羔羊左心室重量增加，心脏IGF-2和IGF-2R基因表达增加。在此，我们研究了ABW和LBW羔羊中IGF-2基因变体的心脏表达、组蛋白乙酰化程度以及IGF-2R下游信号通路中蛋白质的丰度。在21日龄时收集ABW和LBW羔羊左心室的样本。与ABW羔羊相比，LBW羔羊中磷酸化CaMKII蛋白增加，HDAC 4丰度降低。与ABW羔羊相比，LBW羔羊中GATA 4增加，磷酸化肌钙蛋白I丰度降低，它们分别是病理性心脏肥大和收缩力受损或降低的标志物。LBW羔羊中IGF-2R启动子和IGF-2R内含子2差异甲基化区域的H3K9组蛋白乙酰化增加。总之，IGF-2R的组蛋白乙酰化可能导致IGF-2R mRNA表达增加，并随后在生命早期通过CaMKII介导Gαq信号传导，从而增加成年后左心室肥大和心血管疾病的风险。
