| 摘要: |
| 目的：明确卡维地洛对心肌梗死(心梗)后大鼠心肌基质金属蛋白酶（MMP）及其组织抑制因子表达的影响。方法：建立大鼠急性心梗模型，成模后用药组 (n=12)予卡维地洛(10 mg·kg-1·d-1)灌胃，用药42 d。未用药组(n=12)予等量生理盐水灌胃。另设假手术组(n=9)为对照。检测各组大鼠心功能和血流动力学参数，酶谱法测定心室肌MMP-2、MMP-9活性，免疫组化和荧光定量PCR检测心室肌MMP-2、MMP-9、金属蛋白酶组织抑制因子（TIMP-2）蛋白和mRNA表达以及TIMP-1、IL-1β、TNF-α mRNA表达。结果：与假手术组比较，心梗组左室舒张末压（LVEDP）升高、左室压最大上升速率（+dp/dtmax）和最大下降速率（-dp/dtmax）均降低（P<0.01），MMP-2、MMP-9活性增强（P<0.01），MMP-2、MMP-9、TIMP-2蛋白表达增多，MMP-2、MMP-9、TIMP-2、IL-1β mRNA升高（P<0.05），TIMP-1、TNF-α mRNA升高（P<0.01）；与心梗未用药组比较，用药组LVEDP降低（P<0.01），+dp/dtmax、-dp/dtmax升高（P<0.05），MMP-2、 MMP-9的活性降低(P<0.01)。MMP-2、MMP-9、TIMP-2蛋白和mRNA表达减少以及TIMP-1、IL-1β、TNF-α mRNA表达减少。结论：卡维地洛在显著降低MMP-2、MMP-9活性的同时也轻度降低了TIMPs表达；它还可以通过减少IL-1β和TNF-α基因表达，起到降低MMPs分泌的作用，从而预防和逆转心梗后心室重构，改善心功能。 |
| 关键词: 心肌梗死 基质金属蛋白酶 基质金属蛋白酶组织抑制因子 卡维地洛 |
| DOI：10.3724/SP.J.1008.2008.00380 |
| 投稿时间：2007-07-03 |
| 基金项目: |
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| Effect of carvedilol on cardiac metalloproteinases and tissue inhibitors of metalloproteinases after myocardial infarction in rats |
| YI Jing-ming,ZHENG Xing*,CHEN Shao-ping,GUO Zhi-fu |
| (Department of Cardiovasology，Changhai Hospital, Second Military Medical University, Shanghai 200433，China) |
| Abstract: |
| Objective：To investigate the effect of carvedilol on expression of cardiac matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) after myocardial infarction in rats. Methods: An animal model of acute myocardial infarction (AMI) was established by descending left coronary artery ligation in 24 rats and they were divided into carvedilol (10 mg·kg-1·d-1) group (n=12) and normal saline group (n=12). Sham-operated group (n=9) received the same procedure but with no ligation. All animals were treated for 6 weeks via a gastric lavage. Heart function and hemodynamic parameters were determined after 6 weeks．The protein expression of cardiac MMP-2, MMP-9 and TIMP-2 was detected by immunohistochemical analysis in AMI groups, and the MMPs activities were assessed by zymography. Gene expression of myocardial MMPs/TIMPs (MMP-2,-9 and TIMP-1, -2) and cytokines (TNF-α, IL-1β) were measured by real-time quantitative PCR. Results: Compared with Sham-operated group，carvedilol group had significantly higher left ventricular end-diastolic pressure (LVEDP) and lower LV upstroke velocity (+dp/dtmax) and LV descent velocity (-dp/dtmax)（P<0.01）. Activities of MMP-2 and MMP-9, protein expression of MMP-2, MMP-9 and TIMP-2, and mRNA expression of MMP-2, MMP-9, TIMP-1, TIMP-2, IL-1β, and TNF-α were all higher in carvedilol group compared with sham-operated group (P<0.05). Compared with normal saline group, carvedilol group had lower LVEDP（P<0.01）, higher +dp/dtmax, -dp/dtmax(P<0.05),lower activities of MMP-2, MMP-9（P<0.01）, lower protein expression of MMP-2, MMP-9 and TIMP-2, and lower mRNA expression of MMP-2, MMP-9, TIMP-2, IL-1β, TIMP-1, and TNF-α (MMP-9 P<0.01，others P<0.05). Conclusion: Carvedilol can obviously decrease cardiac expression of MMP-2 and MMP-9 and slightly decrease expression of TIMPs; it can also decrease secretion of MMPs through decreasing IL-1β and TNF-α expression,thus prevents myocardial extracellular matrix remodeling,reverses ventricular remodeling,and subsequently improves cardiac function. |
| Key words: myocardial infarction matrix metalloproteinases tissue inhibitors of metalloproteinases carvedilol |
