Spatiotemporal induction of matrix metalloproteinase-9 transcription after discrete myocardial injury

摘要

Radiofrequency (RF) ablation of the myocardium causes discrete sites of injury. RF scars can expand, altering the extracellular matrix (ECM) structure and the continuity of the electrical syncytium of the adjacent myocardium. Matrix metalloproteinases (MMPs), such as MMP-9, contribute to ECM remodeling. However, whether and to what degree transcriptional induction of MMP-9 occurs after myocardial RF injury and the association with electrical conduction patterns after RF injury remains unexplored. This study examined MMP-9 gene promoter (M9PROM) activation after myocardial RF injury using mice in which the M9PROM was fused to a β-galactosidase (β-gal) reporter. RF lesions (0.5-mm probe, 80°C, 30 s) were created on the left ventricular (LV) epicardium of M9PROM mice (n=62) and terminally studied at 1 h, 1 d, 3 d, 7 d, 14 d, and 28 d after RF injury. M9PROM activation was localized through β-gal staining. The RF scar area and the area of β-gal staining were measured and normalized to LV area (planimetry). RF scar size increased from 1 h post-RF-injury values by 7 d and remained higher at 28 d. M9PROM activation became evident at 3 d and peaked at 7 d. Electrical conduction was measured (potentiometric dye mapping) at 7 d after RF injury. Heterogeneities in action potentials and electrical impulse propagation coincident with M9PROM activation were observed after RF injury. For example, conduction proximal to the RF site was slower than that in the remote myocardium (0.15±0.02 vs. 0.83±0.08 mm/ms, P<0.05). Thus, a unique spatiotemporal pattern of MMP-9 transcriptional activation occurred after discrete myocardial injury, which was associated with the development of electrical heterogeneity. Therefore, these findings suggest that changes in a key determinant of extracellular matrix remodeling, in addition to changes in myocardial structure, can contribute to arrhythmogenesis around the region of myocardial injury.—Mukherjee, R., Colbath, G. P., Justus, C. D., Bruce, J. A., Allen, C. M., Hewett, K. W., Saul, J. P., Gourdie, R. G., Spinale, F. G. Spatiotemporal induction of matrix metalloproteinase-9 transcription following discrete myocardial injury.