Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction.
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.
Mukherjee
Rupak
R
Cardiothoracic Surgery, Strom Thurmond Research Bldg., 770 MUSC Complex, Ste. 625, Medical Univ. of South Carolina, Charleston, SC 29425, USA. mukherr@musc.edu
Mingoia
Joseph T
JT
Bruce
James A
JA
Austin
Jeffrey S
JS
Stroud
Robert E
RE
Escobar
G Patricia
GP
McClister
David M
DM
Allen
Claire M
CM
Alfonso-Jaume
Maria A
MA
Fini
M Elizabeth
ME
Lovett
David H
DH
Spinale
Francis G
FG
D000818:Animals; D004452:Echocardiography; D004790:Enzyme Induction; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000201:enzymology* / Q000209:etiology; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology*; D013997:Time Factors; D014158:Transcription, Genetic; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D001616:beta-Galactosidase / Q000378:metabolism
D001616:beta-Galactosidase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9