Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction
Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction
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DOI：
10.1152/ajpheart.01343.2005
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发表时间：
2006-11-01
影响因子：
4.8
通讯作者：
Spinale, Francis G.
中科院分区：
文献类型：
--
作者：
Mukherjee, Rupak;Mingoia, Joseph T.;Spinale, Francis G.
心肌梗死（MI）后心肌重塑与基质金属蛋白酶（MMPs）水平升高有关。两种MMP物质MMP-2和MMP-9的水平在MI后增加，并且这些MMP的转基因缺失减弱MI后左心室（LV）重构。本研究的特点是心肌梗死后MMP-2和MMP-9基因启动子诱导的时空模式。在转基因小鼠中诱导MI，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MI后28天测定报告基因水平。研究了MMP-2和MMP-9启动子诱导的细胞来源的心肌定位。MI后左室内径增大70%（P < 0.05），与左室重构相一致。MMP-2报告小鼠中的β-半乳糖苷酶染色在MI后1天增加，并且在MI后7天进一步增加至LV心外膜面积的64 +/-6%（P < 0.05）。MMP-2启动子激活发生在MI区的成纤维细胞和肌成纤维细胞中。在MMP-9报告小鼠中，MI后3天检测到启动子诱导，并在MI后7天达到峰值（53 +/-6%，P < 0.05），并与梗死周围区域的炎性细胞共定位。虽然MMP-2启动子的激活类似地分布在MI和边界区域，但MMP-9启动子的激活在MI和偏远区域之间的边界处最高。这些独特的研究结果直观地表明，MMP-2和MMP-9基因启动子的激活发生在一个独特的空间关系，参照MI区域和MI后的特征性时间依赖性方式的变化。
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.