Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction
Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction
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DOI：
10.1161/circulationaha.106.612960
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发表时间：
2006-06-27
期刊：
影响因子：
37.8
通讯作者：
Spinale, FG
中科院分区：
文献类型：
--
作者：
Lindsey, ML;Escobar, P;Spinale, FG
背景：基质金属蛋白酶（MMPs）参与心肌梗死（MI）后左心室重构。然而，特定MMPs的具体致病作用仍不清楚。MMP-7在心肌细胞和巨噬细胞中含量丰富，但心肌梗死后MMP-7的功能尚未明确。方法与结果：野生型（WT; n=55）和MMP-7-null (MMP-7(-/-))；N =32)小鼠进行永久性冠状动脉结扎7天。心肌梗死大小相似，但MMP-7（-/-）小鼠的存活率大大提高。生存差异不能归因于左室舒张程度的差异，因为舒张末期容积增加相似。心电图分析显示，心肌梗死后MMP-7（-/-）小鼠PR间期延长，而WT小鼠PR间期延长。在MMP-7（-/-）小鼠中，MMP-7（-/-）小鼠的传导速度降至对照组的78 +/- 6%。在WT小鼠中，较慢的传导速度与间隙连接蛋白connexin-43减少53%相关。通过表面等离子体共振技术确定MMP-7与连接蛋白43的直接结合以剂量依赖的方式发生。通过体内和体外底物分析以及体内注入MMP-7诱导的心律失常，证实了MMP-7对Connexin-43的作用。结论-MMP-7缺失可改善心肌梗死后的存活和心肌传导模式。这是首次报道MMP-7与心肌梗死后重构有关，并证明连接蛋白43是一种新的MMP-7底物。
Background-Matrix metalloproteinases ( MMPs) contribute to left ventricular remodeling after myocardial infarction (MI). Specific causative roles of particular MMPs, however, remain unclear. MMP-7 is abundant in cardiomyocytes and macrophages, but MMP-7 function after MI has not been defined.Methods and Results-Wild-type (WT; n=55) and MMP-7-null (MMP-7(-/-); n=32) mice underwent permanent coronary artery ligation for 7 days. MI sizes were similar, but survival was greatly improved in MMP-7(-/-) mice. The survival difference could not be attributed to differences in left ventricular dilation because end-diastolic volumes increased similarly. ECG analysis revealed a prolonged PR interval in WT but not in MMP-7(-/-) post-MI mice. Post-MI conduction velocity, determined by optically mapping electrical wavefront propagation, decreased to 78 +/- 6% of control for WT and was normalized in MMP-7(-/-) mice. In WT mice, slower conduction velocity correlated with a 53% reduction in the gap junction protein connexin-43. Direct binding of MMP-7 to connexin-43, determined by surface plasmon resonance technology, occurred in a dose-dependent manner. Connexin-43 processing by MMP-7 was confirmed by in silico and in vitro substrate analyses and MMP-7 infusion induced arrhythmias in vivo.Conclusions-MMP-7 deletion results in improved survival and myocardial conduction patterns after MI. This is the first report to implicate MMP-7 in post-MI remodeling and to demonstrate that connexin-43 is a novel MMP-7 substrate.