Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction

Abstract

Myocardial remodeling after myocardial infarction (MI) is associated with increased levels of the matrix metalloproteinases (MMPs). Levels of two MMP species, MMP-2 and MMP-9, are increased after MI, and transgenic deletion of these MMPs attenuates post-MI left ventricular (LV) remodeling. This study characterized the spatiotemporal patterns of gene promoter induction for MMP-2 and MMP-9 after MI. MI was induced in transgenic mice in which the MMP-2 or MMP-9 promoter sequence was fused to the beta-galactosidase reporter, and reporter level was assayed up to 28 days after MI. Myocardial localization with respect to cellular sources of MMP-2 and MMP-9 promoter induction was examined. After MI, LV diameter increased by 70% (P < 0.05), consistent with LV remodeling. beta-Galactosidase staining in MMP-2 reporter mice was increased by 1 day after MI and increased further to 64 +/- 6% of LV epicardial area by 7 days after MI (P < 0.05). MMP-2 promoter activation occurred in fibroblasts and myofibroblasts in the MI region. In MMP-9 reporter mice, promoter induction was detected after 3 days and peaked at 7 days after MI (53 +/- 6%, P < 0.05) and was colocalized with inflammatory cells at the peri-infarct region. Although MMP-2 promoter activation was similarly distributed in the MI and border regions, activation of the MMP-9 promoter was highest at the border between the MI and remote regions. These unique findings visually demonstrated that activation of the MMP-2 and MMP-9 gene promoters occurs in a distinct spatial relation with reference to the MI region and changes in a characteristic time-dependent manner after MI.

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

“…MMP-2 transcriptional activation occurred within the MI region, and persistent activation into the remote, viable myocardium could be observed by 1 mo post-MI. In this study, activation of the MMP-9 promoter was colocalized to inflammatory cells, whereas MMP-2 promoter activation was localized to cell types consistent with a fibroblast phenotype (286). These reporter studies clearly demonstrated that a robust and prolonged increase in MMP transcriptional activity occurs following MI and extends into the viable, normally perfused myocardium.…”

“…In other studies, the full-length promoter region for MMP-2 or MMP-9 fused to a reporter has been permanently ligated into the murine system (4,220,286). With the use of this approach, MMP transcriptional activity can be quantified as well as localized.…”

“…With the use of this approach, MMP transcriptional activity can be quantified as well as localized. For example, using the MMP-2 or MMP-9 reporter mice, the spatiotemporal transcriptional activity could be visualized within the intact heart following MI (286). As shown in Figure 23, MMP-9 transcriptional activation occurred within and around the MI region early following coronary ligation and was particularly prominent within the border region.…”

“…The full-length human MMP-2 or MMP-9 promoter was ligated to the ␤-galactosidase reporter and fused into mice (4,220,286). This approach provides for spatial localization of MMP-2 and MMP-9 promoter activity.…”

Biomarkers of apoptosis, inflammation, and cardiac extracellular matrix remodelling in the prognosis of heart failure

“…A number of different MMPs released from inflammatory cells and myofibroblast allow nascent scar formation. However, continuous and persistent release of MMPs beyond this initial healing process results in extracorporeal matrix instability, particularly in the infarct-viable border zone, and during remodelling of the extracellular matrix in remote healthy myocardium [16].…”