Mukherjee Rupak, Mingoia Joseph T, Bruce James A, Austin Jeffrey S, Stroud Robert E, Escobar G Patricia, McClister David M, Allen Claire M, Alfonso-Jaume Maria A, Fini M Elizabeth, Lovett David H, Spinale Francis G
Cardiothoracic Surgery, Strom Thurmond Research Bldg., 770 MUSC Complex, Ste. 625, Medical Univ. of South Carolina, Charleston, SC 29425, USA.
Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2216-28. doi: 10.1152/ajpheart.01343.2005. Epub 2006 Jun 9.
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.
心肌梗死后的心肌重塑与基质金属蛋白酶（MMPs）水平升高有关。心肌梗死后，两种MMP，即MMP-2和MMP-9的水平会升高，而这些MMP的转基因缺失可减轻心肌梗死后的左心室（LV）重塑。本研究对心肌梗死后MMP-2和MMP-9基因启动子诱导的时空模式进行了表征。在转基因小鼠中诱导心肌梗死，其中MMP-2或MMP-9启动子序列与β-半乳糖苷酶报告基因融合，并在心肌梗死后长达28天检测报告基因水平。研究了MMP-2和MMP-9启动子诱导的细胞来源在心肌中的定位。心肌梗死后，左心室直径增加了70%（P<0.05），与左心室重塑一致。MMP-2报告基因小鼠中的β-半乳糖苷酶染色在心肌梗死后1天增加，并在心肌梗死后7天进一步增加至左心室心外膜面积的64±6%（P<0.05）。MMP-2启动子激活发生在梗死区域的成纤维细胞和肌成纤维细胞中。在MMP-9报告基因小鼠中，在心肌梗死后3天检测到启动子诱导，并在心肌梗死后7天达到峰值（53±6%，P<0.05），并与梗死周边区域的炎症细胞共定位。尽管MMP-2启动子激活在梗死区域和边界区域的分布相似，但MMP-9启动子激活在梗死区域与远隔区域之间的边界处最高。这些独特的发现直观地表明，MMP-2和MMP-9基因启动子的激活相对于梗死区域以独特的空间关系发生，并在心肌梗死后以特征性的时间依赖性方式变化。
