1型血管紧张素II受体拮抗剂对心肌梗死后心脏表型调节的抑制作用。

Inhibition by angiotensin II type 1 receptor antagonist of cardiac phenotypic modulation after myocardial infarction.

作者信息

Hanatani A, Yoshiyama M, Kim S, Omura T, Toda I, Akioka K, Teragaki M, Takeuchi K, Iwao H, Takeda T

机构信息

First Department of Internal Medicine, Osaka City University Medical School, Japan.

出版信息

J Mol Cell Cardiol. 1995 Sep;27(9):1905-14. doi: 10.1016/0022-2828(95)90013-6.

DOI:10.1016/0022-2828(95)90013-6

PMID:8523451

Abstract

The purpose of this study was to examine the cardiac phenotype and remodeling after myocardial infarction and the effect of the angiotensin II type 1 (AT1) receptor antagonist (TCV-116) on the gene expression. Myocardial infarction in rats was produced by ligation of the coronary artery. TCV-116 (10 mg/kg/day) was administered orally to rats from 1 day after myocardial infarction. At 1, 2 and 3 weeks after myocardial infarction, blood pressure and heart rate were measured, and the heart was removed. The left ventricle was measured for infarct size and weight, and then the total RNA from the non-ischemic left ventricle was extracted. mRNAs in the non-ischemic left ventricle were measured by Northern blot analysis. The weight of the non-ischemic left ventricle was significantly increased 3 weeks after infarction. This was completely prevented by TCV-116 treatment. mRNA levels for beta-myosin heavy chain (beta-MHC), atrial natriuretic polypeptide (ANP), collagen types I and III and transforming growth factor-beta 1 (TGF-beta 1) in the non-ischemic left ventricle were increased by a factor of 3.0, 6.7, 7.9, 4.0 and 1.4 (P < 0.01), respectively, 1 week after infarction. There was no increase in alpha-skeletal actin mRNA at 1 and 2 weeks, but it was increased by a factor of 2.9 (P < 0.05) at 3 weeks. On the other hand, there was no change in alpha-MHC mRNA during the 3 weeks. TCV-116 significantly suppressed the increased gene expression of beta-MHC and alpha-skeletal actin in the non-ischemic myocardium at all time points, and also suppressed the expression of ANP at 2 and 3 weeks. However, TCV-116 failed to inhibit the expression of collagen I and III mRNAs at 1 and 3 weeks. These results show that myocardial infarction causes a rapid shift of myocytes to fetal phenotype and a rapid activation of collagen genes in the non-ischemic myocardium. AT1 receptor may be responsible for the phenotypic modulation of myocytes following myocardial infarction.

摘要

本研究的目的是检测心肌梗死后的心脏表型和重塑情况，以及血管紧张素II 1型（AT1）受体拮抗剂（TCV-116）对基因表达的影响。通过结扎冠状动脉在大鼠中制造心肌梗死。从心肌梗死后第1天起，对大鼠口服给予TCV-116（10毫克/千克/天）。在心肌梗死后1、2和3周，测量血压和心率，并取出心脏。测量左心室的梗死面积和重量，然后从非缺血性左心室中提取总RNA。通过Northern印迹分析测量非缺血性左心室中的mRNA。梗死3周后，非缺血性左心室的重量显著增加。TCV-116治疗可完全预防这种情况。梗死1周后，非缺血性左心室中β-肌球蛋白重链（β-MHC）、心钠素（ANP）、I型和III型胶原蛋白以及转化生长因子-β1（TGF-β1）的mRNA水平分别增加了3.0、6.7、7.9、4.0和1.4倍（P<0.01）。在1周和2周时，α-骨骼肌动蛋白mRNA没有增加，但在3周时增加了2.9倍（P<0.05）。另一方面，在这3周内α-MHC mRNA没有变化。TCV-116在所有时间点均显著抑制非缺血心肌中β-MHC和α-骨骼肌动蛋白增加的基因表达，并且在2周和3周时也抑制ANP的表达。然而，TCV-116在1周和3周时未能抑制I型和III型胶原蛋白mRNA的表达。这些结果表明，心肌梗死导致非缺血心肌中的心肌细胞迅速转变为胎儿表型，并迅速激活胶原蛋白基因。AT1受体可能负责心肌梗死后心肌细胞的表型调节。