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

1 Division of Cardiothoracic Surgery, Medical University of South Carolina, and 4 Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina; 2 McKnight Vision Research Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida; and 3 Department of Medicine, Veterans Affairs Medical Center/University of California, San Francisco, California Submitted 20 December 2005 ; accepted in final form 5 June 2006 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 -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. -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. structure; remodeling; matrix metalloproteinases Address for reprint requests and other correspondence: R. Mukherjee, Cardiothoracic Surgery, Strom Thurmond Research Bldg., 770 MUSC Complex, Ste. 625, Medical Univ. of South Carolina, Charleston, SC 29425 (e-mail: mukherr{at}musc.edu )