Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction

Article

关键词: SURFACE-PLASMON RESONANCE;    HEART-FAILURE;    GAP-JUNCTIONS;    VENTRICULAR-TACHYCARDIA;    IMPULSE PROPAGATION;    BORDER ZONE;    MATRILYSIN;    MICE;    MODEL;    RAT;   

DOI  :  10.1161/CIRCULATIONAHA.106.612960

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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