Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction
Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction
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DOI：
10.1152/ajpheart.00207.2003
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发表时间：
2003-09-01
影响因子：
4.8
通讯作者：
Takeshita, A
中科院分区：
文献类型：
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作者：
Hayashidani, S;Tsutsui, H;Takeshita, A
基质金属蛋白酶-2（MMP-2）在心肌梗死（MI）后和心力衰竭时均显著过表达。然而，其在这些条件下的病理生理学意义仍不清楚。因此，我们研究了靶向删除MMP-2对MI后左心室（LV）重构和衰竭的影响。通过结扎左冠状动脉，在10至12周龄的雄性MMP-2敲除（KO）和同胞野生型（WT）小鼠中产生前壁MI。到第28天，MI导致与LV腔扩张和功能障碍相关的死亡率显著增加。MMP-2敲除小鼠的存活率显著高于WT小鼠（56% vs. 85%，P < 0.05），尽管梗死面积（50 +/- 3% vs. 51 +/-3%，P =不显著）、心率和动脉血压相当。KO小鼠在MI后7天内发生LV破裂的发生率显著较低（10% vs.39%，P < 0.05）。通过超声心动图，KO小鼠在MI后表现出较少的LV腔扩张和改善的缩短分数。冠状动脉结扎后，WT小鼠的LV酶谱MMP-2水平显著升高;然而，KO小鼠完全阻止了这一现象。相比之下，MI后左心室酶谱MMP-9水平的增加在KO和WT小鼠之间相似。因此，认为MMP-2活化有助于MI后早期心脏破裂以及晚期LV重塑。因此，抑制MMP-2活化可能是一种潜在的有用的治疗策略，以管理MI后的心脏。
Matrix metalloproteinase-2 (MMP-2) is prominently overexpressed both after myocardial infarction (MI) and in heart failure. However, its pathophysiological significance in these conditions is still unclear. We thus examined the effects of targeted deletion of MMP-2 on post-MI left ventricular (LV) remodeling and failure. Anterior MI was produced in 10- to 12-wk-old male MMP-2 knockout (KO) and sibling wild-type (WT) mice by ligating the left coronary artery. By day 28, MI resulted in a significant increase in mortality in association with LV cavity dilatation and dysfunction. The MMP-2 KO mice had a significantly better survival rate than WT mice (56% vs. 85%, P < 0.05), despite a comparable infarct size (50 +/- 3% vs. 51 +/- 3%, P = not significant), heart rate, and arterial blood pressure. The KO mice had a significantly lower incidence of LV rupture ( 10% vs. 39%, P < 0.05), which occurred within 7 days of MI. The KO mice exerted less LV cavity dilatation and improved fractional shortening after MI by echocardiography. The LV zymographic MMP-2 level significantly increased in WT mice after coronary artery ligation; however, this was completely prevented in KO mice. In contrast, the increase in the LV zymographic MMP-9 level after MI was similar between KO and WT mice. MMP-2 activation is therefore considered to contribute to an early cardiac rupture as well as late LV remodeling after MI. The inhibition of MMP-2 activation may therefore be a potentially useful therapeutic strategy to manage post-MI hearts.