Sun Y, Zhang J Q, Zhang J, Ramires F J
Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia, MO, USA.
J Mol Cell Cardiol. 1998 Aug;30(8):1559-69. doi: 10.1006/jmcc.1998.0721.
Tissue repair following myocardial infarction (MI) eventuates in fibrous tissue formation at the site of myocyte necrosis. Following a large transmural MI, fibrosis appears remote to the infarct site. This is associated with extensive tissue remodeling that adversely affects ventricular diastolic function. Substances involved in promoting fibrous tissue formation at MI and remote sites are under investigation. Angiotensin II (AngII), generated at sites of repair, has been implicated. However, its regulatory role on fibrous tissue formation remains uncertain. In the present study we sought to determine whether AngII is correlated to transforming growth factor beta 1 (TGF-beta1) expression, a regulator of fibrous tissue formation, at these sites of tissue repair. We studied: (1) localization and expression of angiotensin converting enzyme (ACE), AngII receptors, TGF-beta1 mRNA and its receptors in the infarcted rat heart; and (2) effect of AngII on TGF-beta1 synthesis by chronic blockade of AT1 receptors began at the time of surgery by losartan in rats with MI. Hearts were studied at 4 weeks post-MI. We found: (1) low-density ACE, AngII and TGF-beta1 receptor binding and low mRNA for type I collagen and TGF-beta1 in the normal heart; (2) fibrosis at sites of MI and remote to it, including endocardium and fibrosis of intraventricular septum, interstitial fibrosis of non-infarcted myocardium and fibrosis of visceral pericardium; (3) markedly increased (P<0.01) and colocalized ACE, AngII and TGF-beta1 receptor binding, type I collagen and TGF-beta1 mRNA at MI and remote sites of repair; (4) increased TGF-beta1 concentration (P<0. 01) at these sites; and (5) attenuated TGF-beta1 and type I collagen gene expression (P<0.01) at these sites in rats receiving losartan. These observations suggest locally generated AngII via ATi receptor binding is correlated to TGF-beta1 expression and synthesis at sites of repair and remote sites in the infarcted rat heart. The mechanism responsible for the role of AngII in TGF-beta1 remains to be elucidated.
心肌梗死（MI）后的组织修复最终会在心肌细胞坏死部位形成纤维组织。大面积透壁性心肌梗死后，纤维化出现在远离梗死部位的区域。这与广泛的组织重塑有关，会对心室舒张功能产生不利影响。参与促进心肌梗死部位及远处纤维组织形成的物质正在研究中。在修复部位产生的血管紧张素II（AngII）被认为与之有关。然而，其对纤维组织形成的调节作用仍不确定。在本研究中，我们试图确定在这些组织修复部位，AngII是否与纤维组织形成的调节因子转化生长因子β1（TGF-β1）的表达相关。我们研究了：（1）血管紧张素转换酶（ACE）、AngII受体、TGF-β1 mRNA及其受体在梗死大鼠心脏中的定位和表达；（2）通过在心肌梗死大鼠手术时开始用氯沙坦慢性阻断AT1受体，观察AngII对TGF-β1合成的影响。在心肌梗死后4周对心脏进行研究。我们发现：（1）正常心脏中低密度的ACE、AngII和TGF-β1受体结合以及I型胶原蛋白和TGF-β1的低mRNA水平；（2）心肌梗死部位及其远处的纤维化，包括心内膜和室间隔纤维化、非梗死心肌的间质纤维化和脏层心包纤维化；（3）在心肌梗死部位及远处修复部位，ACE、AngII和TGF-β1受体结合、I型胶原蛋白和TGF-β1 mRNA显著增加（P<0.01）且共定位；（4）这些部位的TGF-β1浓度增加（P<0.01）；（5）在接受氯沙坦的大鼠中，这些部位的TGF-β1和I型胶原蛋白基因表达减弱（P<0.01）。这些观察结果表明，通过AT1受体结合在局部产生的AngII与梗死大鼠心脏修复部位及远处部位的TGF-β1表达和合成相关。AngII在TGF-β1中发挥作用的机制仍有待阐明。
