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1 Div of Cardiothoracic Surgery Research, Medical University of South Carolina, Charleston, South Carolina, United States
2 McKnight Vision Research Center, Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States
3 Department of Medicine, Veterans Affairs Medical Center, UCSF, San Francisco, California, United States
4 Div of Cardiothoracic Surgery Research, Medical University of South Carolina, Charleston, South Carolina, United States; Ralph H. Johnson Veteran's Adminstration Medical Center, Charleston, South Carolina, United States
* To whom correspondence should be addressed. E-mail: mukherr{at}musc.edu.
Background: Myocardial remodeling following 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 post-MI and transgenic deletion of these MMPs attenuate post-MI left ventricular (LV) remodeling. This study characterized the spatiotemporal patterns of gene promoter induction for MMP-2 and MMP-9 post-MI.
Methods and Results: MI was induced in transgenic mice in which either the MMP-2 or the MMP-9 promoter sequences were fused to the
-galactosidase reporter and reporter levels was assayed up to 28 days post-MI. Myocardial localization with respect to cellular sources of MMP-2 and MMP-9 promoter induction were examined. Post-MI, LV diameter increased by 70% (p<0.05), consistent with LV remodeling.
-galactosidase staining in the MMP-2 reporter mice was increased by 1 day post-MI, and increased further to 64±6% of LV epicardial area by 7 days (p<0.05). MMP-2 promoter activation occurred in fibroblasts and myofibroblasts in the MI region. In the MMP-9 reporter mice, promoter induction was detected after 3 days post-MI and peaked at 7 days post-MI (53±6%, p<0.05) and was colocalized with inflammatory cells at the peri-infarct region. While 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.
Conclusions: These unique findings visually demonstrated that activation of the MMP-2 and MMP-9 gene promoters occurs not only in a distinct spatial relation with reference to the MI region but also follows characteristic time-dependent changes post-MI.
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