Molecular Biological Approach to the Genesis of Myocardial Remodeling After Myocardial Infarction

背景已知，当存在心肌梗死或压力超负荷时，心脏会导致重构。心肌肾素-血管紧张素系统(RAS)被认为参与了这种改变的发生。在一项临床试验中，使用血管紧张素转换酶抑制剂长期治疗充血性心力衰竭患者，其主要原因是心肌梗死，已证明提高了存活率。在这项研究中，我们用分子生物学技术评估了抑制RAS对实验性大鼠心肌梗死的影响。材料和方法雄性Wistar大鼠左冠状动脉结扎造成心肌梗死。术后1~12周处死大鼠，分离心脏，用硫代巴比妥酸乙酯和伊文思蓝染色判断心肌组织存活或梗死，并对心肌组织进行如下评价：胶原含量、血管紧张素转换酶…逆转录聚合酶链式反应(RT-PCR)检测血管紧张素转换酶(ACE)和血管紧张素转换酶1型受体(AT1)的表达。术后3天至12周每天给予AT1受体阻滞剂E-4177(3或10 mg/kg/d)或血管紧张素转换酶抑制剂依那普利(3或15 mg/kg/d)，并与同龄未治疗大鼠进行比较。[结果]心肌梗死大鼠术后4~12周心脏重量、心肌胶原含量、血管紧张素转换酶活性、血管紧张素转换酶1受体结合量及血管紧张素转换酶和血管紧张素转换酶1的mRNA表达均高于假手术组。用大剂量E-4177或依那普利治疗后，上述改变明显恢复正常或不正常。尽管所有未经治疗的心肌梗死大鼠胸腔积液均超过3毫升，但经治疗的心肌梗死组大鼠未见胸腔积液。心肌梗死大鼠心肌细胞膜Na~+-Ca~(2+)~(2+)-Gt~(2+)交换活性在未经治疗的心肌梗死大鼠心肌细胞膜Na~+-Ca~(2+)~(2+)-Gt~(2+)交换活性受到抑制，而治疗组则恢复正常。这些改变与压力超负荷心肌肥厚模型相同。最后，在治疗和未治疗的梗塞大鼠之间，梗塞面积没有显著差异。结论心肌梗死后存活的心肌肥大和纤维化，即所谓的重构，心脏RAS似乎与这些改变的发生有关。提示AT1受体拮抗剂和ACE抑制剂等具有抗RAS作用的药物在治疗心肌梗死和充血性心力衰竭后心脏重构方面具有重要作用。较少

*Background* It is known that a heart wil be lead to a remodeling when myocardial infarction or pressure overload is present. A myocardial renin-angiotensin system (RAS) is suggested to participate to a genesis of this alteration. A long term treatment of patients with congestive heart failure, main cause of which were myocardial infarction, with angiotensin converting enzyme inhibitor has demonstrated to increase a survival rate in a clinical trial. We evaluated with a molecular biological technique the effects of a inhibition of RAS in experimentally produced myocardial infarctions in rats in this study. *Materials and Methods* A myocardial infarction was produced by a ligation of a left coronary artery at the close to its begining of a male Wistar rat. The heart was isolated at 1 to 12 weeks after the surgery, and the heart was stained with TTC and Evans Blue to devide the tissue into survival or infarcted, then the tissue were provided toevaluate followings ; collagen content, ACE … More activity, angiotensin II receptor binding capacity, mRNA expressions of ACE and angiotensin type 1 receptor (AT1) by a reverse transcriptase polymarase chain reaction (RT-PCR). Rats had been administered with an AT1 blockade of E-4177 (3 or 10 mg/kg/day) or an ACE inhibitor of enalapril (3 or 15 mg/kg/day) daily from the 3 days after the surgery to 12 weeks, then compared with the nontreated rats at the same age. *Results* Heart weight, myocardial collagen content, ACE activity, AT1 receptor binding capacity, and mRNA expressions of ACE and AT1 had been increased in the rats with myocardial infarction from 4 weeks to 12 weeks after the surgery compared with sham operated rats. These alterations were normalized or subnormalized remarkablly with the treatments of high dose E-4177 or enalapril. Although over 3 ml of pleural effusion was found in all nontreated rats with myocardial infarction, there were no rats with such findings in treated myocardial groups. Sarcolemmal Na^+-Ca^<2+> exchange activity was depressed in nontreated myocadial infarcted rats, and this was found to be normalized in treated groups. These alterations were in a same manner as pressure overload cardiac hypertrophy models. Finally, there was no remarkable difference in infarction size between treated and nontreated infarcted rats. *Conclusions* Survived myocardium after myocardial infarction was caused hypertrophy and fibrosis, so called remodelling, and cardiac RAS seemed to concern the genesis of these alterations. It is suggested that the drugs which have anti-RAS action such as an AT1 blockade and an ACE inhibitor will be important to treat the cardiac remodelling after myocardial infarction and congestive heart failure. Less