大鼠心力衰竭时心肌双糖链蛋白聚糖的诱导——一种受AT(1)受体拮抗剂作用的细胞外基质成分

Induction of myocardial biglycan in heart failure in rats--an extracellular matrix component targeted by AT(1) receptor antagonism.

作者信息

Ahmed Mohammed Shakil, Øie Erik, Vinge Leif Erik, Yndestad Arne, Andersen G Geir Øystein, Andersson Yvonne, Attramadal Toril, Attramadal Håvard

机构信息

MSD Cardiovascular Research Centre, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway.

出版信息

Cardiovasc Res. 2003 Dec 1;60(3):557-68. doi: 10.1016/j.cardiores.2003.08.017.

DOI:10.1016/j.cardiores.2003.08.017

PMID:14659801

Abstract

OBJECTIVE

Cardiac remodelling associated with congestive heart failure typically involves dilatation of the ventricular cavities, cardiomyocyte hypertrophy and alterations of extracellular matrix. Biglycan is an extracellular proteoglycan with several recently appreciated functions including cell adhesion, collagen fibril assembly, and growth factor interactions. The aims of this study were to investigate the regulation of biglycan expression and to elucidate the site(s) of synthesis of biglycan in myocardial tissue in an experimental model of heart failure (HF).

METHODS

Myocardial tissue samples were obtained from rats with myocardial infarction (MI) subsequent to ligation of the left coronary artery. Northern blot analysis and real-time quantitative RT-PCR were employed to investigate mRNA levels. The cellular distribution of biglycan was analysed by in situ hybridisation and immunohistochemistry.

RESULTS

Myocardial biglycan mRNA levels in non-ischemic tissue of both left and right ventricles of heart failure rats were substantially elevated as compared to sham-operated rats. Although expression levels peaked 7 days after MI (13-fold increase compared to the sham group, P<0.05), substantial elevations of biglycan mRNA were observed throughout the study period. Analysis of cellular distribution revealed that biglycan expression was confined to myocardial fibroblasts and vascular endothelial cells. In cardiac fibroblasts isolated from failing hearts, biglycan mRNA levels were markedly elevated compared with fibroblasts from sham-operated rats. In addition, in rats with ischemic heart failure treatment with the AT(1) receptor antagonist losartan (12.5 mg.kg(-1) b.i.d. per os, for 25 days) prevented the increase of myocardial biglycan as well as TGF-beta(1) mRNA.

CONCLUSION

This report demonstrates global induction of myocardial biglycan mRNA in heart failure. Myocardial biglycan expression could be targeted by AT(1) receptor antagonism, an intervention well documented to halt cardiac remodelling in heart failure. Furthermore, the study provides evidence that angiotensin II is a regulator of biglycan expression in cardiac fibroblasts.

摘要

目的

与充血性心力衰竭相关的心脏重塑通常涉及心室腔扩张、心肌细胞肥大以及细胞外基质改变。双糖链蛋白聚糖是一种细胞外蛋白聚糖，具有多种近期被认识到的功能，包括细胞黏附、胶原纤维组装以及生长因子相互作用。本研究的目的是调查双糖链蛋白聚糖表达的调控，并阐明在心力衰竭（HF）实验模型中心肌组织中双糖链蛋白聚糖的合成部位。

方法

从左冠状动脉结扎后发生心肌梗死（MI）的大鼠获取心肌组织样本。采用Northern印迹分析和实时定量RT-PCR研究mRNA水平。通过原位杂交和免疫组织化学分析双糖链蛋白聚糖的细胞分布。

结果

与假手术大鼠相比，心力衰竭大鼠左、右心室非缺血组织中的心肌双糖链蛋白聚糖mRNA水平显著升高。尽管MI后7天表达水平达到峰值（与假手术组相比增加13倍，P<0.05），但在整个研究期间均观察到双糖链蛋白聚糖mRNA的显著升高。细胞分布分析显示，双糖链蛋白聚糖表达局限于心肌成纤维细胞和血管内皮细胞。与假手术大鼠的成纤维细胞相比，从衰竭心脏分离的心脏成纤维细胞中双糖链蛋白聚糖mRNA水平显著升高。此外，在缺血性心力衰竭大鼠中，用AT(1)受体拮抗剂氯沙坦（12.5 mg·kg(-1)，每日两次口服，共25天）治疗可防止心肌双糖链蛋白聚糖以及TGF-β(1) mRNA的增加。