Lindsey Merry L, Escobar G Patricia, Mukherjee Rupak, Goshorn Danielle K, Sheats Nina J, Bruce James A, Mains I Matthew, Hendrick Jennifer K, Hewett Kenneth W, Gourdie Robert G, Matrisian Lynn M, Spinale Francis G
Cardiology Division, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, Mail Code 7872, San Antonio, TX 78229-3900, USA.
Circulation. 2006 Jun 27;113(25):2919-28. doi: 10.1161/CIRCULATIONAHA.106.612960. Epub 2006 Jun 12.
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.
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.
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.
基质金属蛋白酶（MMPs）参与心肌梗死（MI）后的左心室重塑。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大量存在，但MI后MMP-7的功能尚未明确。
野生型（WT；n = 55）和MMP-7基因敲除（MMP-7-/-；n = 32）小鼠接受永久性冠状动脉结扎7天。MI大小相似，但MMP-7-/-小鼠的存活率显著提高。存活率差异不能归因于左心室扩张的差异，因为舒张末期容积的增加相似。心电图分析显示，MI后WT小鼠的PR间期延长，而MMP-7-/-小鼠则没有。通过光学映射电波形传播确定的MI后传导速度，WT小鼠降至对照的78±6%，而MMP-7-/-小鼠恢复正常。在WT小鼠中，较慢的传导速度与间隙连接蛋白连接蛋白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直接结合呈剂量依赖性。通过计算机模拟和体外底物分析证实了MMP-7对连接蛋白43的加工，并且MMP-7输注在体内诱发心律失常。
MMP-7缺失可提高MI后的存活率并改善心肌传导模式。这是首次报道MMP-7参与MI后重塑，并证明连接蛋白43是一种新的MMP-7底物。
