Connective-tissue growth factor - a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats
Connective-tissue growth factor - a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats
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DOI：
10.1016/j.yjmcc.2003.12.004
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发表时间：
2004-03-01
影响因子：
5
通讯作者：
Attramadal, H
中科院分区：
文献类型：
--
作者：
Ahmed, MS;Oie, E;Attramadal, H
心力衰竭(HF)心肌重构的病理生理机制尚不清楚。通过对缺血型心力衰竭大鼠和对照组大鼠心肌组织的差异显示，我们确定了编码结缔组织生长因子(CTGF)的mRNA在心肌中的强烈诱导。本研究的目的是探讨衰竭心肌组织中CTGF的合成部位和诱导机制。研究表明，在实验性心肌梗死(MI)大鼠的左、右室非缺血组织中，CTGF的mRNA和蛋白的表达显著增加。心肌CTGF mRNA的表达从早期心肌梗死后HF向慢性HE过渡，原位杂交和免疫组织化学分析显示CTGF仅表达于非缺血心肌组织的成纤维细胞和内皮细胞。在随后的实验中，心肌梗死大鼠随机接受血管紧张素受体拮抗剂氯沙坦(12.5 mg/kg，b.i.d)治疗。每个OS)或车辆。氯沙坦可减轻心肌梗死后大鼠心肌肥厚，改善血流动力学，并阻止心肌CTGF mRNA的诱导。为探讨血管紧张素Ⅱ(Ang II)刺激大鼠心肌成纤维细胞CTGF mRNA表达的细胞基础，用Ang II(10(-7)M)刺激原代培养的大鼠心肌成纤维细胞。实时逆转录聚合酶链式反应和免疫印迹分析表明，Ang II可诱导大鼠心脏成纤维细胞CTGF mRNA和蛋白在AT受体介导下快速升高。此外，CTGF在体外还能刺激成纤维细胞的增殖。综上所述，本研究表明CTGF是Ang II通过心脏成纤维细胞上的AT受体介导的心衰心肌重塑的心肌效应因子。(C)2003爱思唯尔有限公司。保留所有权利。
The pathophysiologic mechanisms of myocardial remodeling in heart failure (HF) remain poorly understood. Using differential mRNA display of myocardial tissue from rats with ischemic HF vs. controls we identified robust myocardial induction of the mRNA encoding connective tissue growth factor (CTGF). The aim of this study was to investigate the sites of synthesis and the mechanisms of induction of CTGF in failing myocardial tissue. The study demonstrates that myocardial expression of CTGF mRNA and protein is substantially elevated in non-ischemic tissue from both the left and the right ventricles of rats with experimentally induced myocardial infarction (MI). The induction of myocardial CTGF mRNA was shown to transcend from early post-infarction HF to chronic HE In situ hybridization and immunohistochemical analysis of myocardial tissue sections demonstrated expression of CTGF confined to fibroblasts and endothelial cells of non-ischemic myocardial tissue. In subsequent experiments rats subjected to MI were randomized to treatment with the AT, angiotensin receptor antagonist losartan (12.5 mg/kg b.i.d. per os) or vehicle. Losartan attenuated ventricular hypertrophy, improved hemodynamics, and prevented the induction of myocardial CTGF mRNA observed in rats post-MI. To provide the cellular basis of Ang II-stimulated CTGF mRNA expression, primary cultures of rat myocardial fibroblasts were stimulated with Ang II (10(-7) M). Real-time reverse transcription-polymerase chain reaction and western blot analysis demonstrate that Ang II induces rapid, AT, receptor-mediated elevations of CTGF mRNA and protein in rat cardiac fibroblasts. Furthermore, CTGF was shown to stimulate fibroblast proliferation in vitro. In conclusion, this study demonstrates that CTGF is a myocardial effector of Ang II-induced myocardial remodeling in HF mediated via AT, receptors situated on cardiac fibroblasts. (C) 2003 Elsevier Ltd. All rights reserved.