Discordant activation of gene promoters for matrix metalloproteinases and tissue inhibitors of the metalloproteinases following myocardial infarction.
BACKGROUND
Left ventricular (LV) remodeling following myocardial infarction (MI) is associated with increased levels of specific matrix metalloproteinases (MMPs) and relative reduction of endogenous tissue inhibitors of the MMPs (TIMPs). However, transcriptional mechanisms for the disparate post-MI MMP/TIMP expression remain unknown. Using murine constructs designed to report gene promoter activation, this study tested the hypothesis that distinctly different temporal profiles of MMP-2, MMP-9, and TIMP-1 transcription occurs post-MI.


RESULTS
Transcriptional activity (β-galactosidase (β-gal) reporter constructs) of MMP-2 (n = 49), MMP-9 (n = 62), or TIMP-1 (n = 40) was assayed at 1 h (acute), and 1-28 d after MI (coronary ligation) in transgenic reporter mice. At 7 d post-MI, the area of promoter activation normalized to LV area was increased from acute values for MMP-2 (63.4 ± 5.8 versus 1.1% ± 1.0%, P < 0.05) and MMP-9 (53.1 ± 6.1 versus 1.3% ± 0.9%, P < 0.05). While TIMP-1 promoter activation at 7 d post-MI increased from acute values (3.6 ± 1.3 versus 0.3% ± 0.5%, P < 0.05), this increase was smaller than that for MMP-2 or MMP-9 (both P < 0.05). MMP-2 promoter activation peaked in the MI region at 7 d post-MI and MMP-9 promoter activation was highest in the border region at 7 and 14 d post-MI. TIMP-1 promoter activation peaked within the MI region at 7 d post-MI and within the remote region at 14 d post-MI.


CONCLUSIONS
These findings provided direct in vivo evidence that discordant changes in temporal and spatial patterns of MMP/TIMP transcription occurs with MI. Restoration of TIMP-1 promoter activation may represent a molecular therapeutic target to attenuate/prevent adverse post-MI LV remodeling.
Mukherjee
Rupak
R
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USA. mukherr@musc.edu
Snipes
Jonathan M
JM
Saunders
Stuart M
SM
Zavadzkas
Juozas A
JA
Spinale
Francis G
FG
D000818:Animals; D003331:Coronary Vessels / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D008026:Ligation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling; D001616:beta-Galactosidase / Q000378:metabolism
D019715:Tissue Inhibitor of Metalloproteinase-1; D001616:beta-Galactosidase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9