Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage.
Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage.
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DOI：
10.1038/srep09504
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发表时间：
2015-05-08
影响因子：
4.6
通讯作者：
Veeravalli KK
中科院分区：
文献类型：
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作者：
Chelluboina B;Warhekar A;Dillard M;Klopfenstein JD;Pinson DM;Wang DZ;Veeravalli KK
这项研究强调了MMP-12在缺血性卒中中可能的病理作用。雄性大鼠进行两小时的大脑中动脉闭塞（MCAO）程序。再灌注24小时后，向这些大鼠给予表达MMP-12 shRNA的质粒制剂。结果显示，MCAO大鼠中MMP-12显著上调（在缺血后第1、3、5、7天分别约为47、58、143和265倍）。MMP-12表达定位于神经元，少突胶质细胞和小胶质细胞，但不是星形胶质细胞。MMP-12的转录失活显著减小了梗死面积。MMP-12敲低后，与未治疗的MCAO大鼠相比，梗死面积百分比从62.87 ± 4.13减少到34.67 ± 5.39。MMP-12基因敲低后，缺血大鼠脑内髓鞘碱性蛋白表达增加，MMP-9活性降低。此外，MMP-12敲低后，凋亡程度显著降低。MMP-12敲除后，MCAO大鼠同侧区域的TNFα表达降低，此外TNFα信号下游的凋亡分子蛋白表达也降低。局灶性脑缺血后MMP-12的特异性敲低提供了神经保护，其可以通过降低MMP-9活化和髓鞘降解以及抑制细胞凋亡来介导。
This study highlights the possible pathological role of MMP-12 in the context of ischemic stroke. Male rats were subjected to a two-hour middle cerebral artery occlusion (MCAO) procedure. MMP-12 shRNA expressing plasmid formulation was administered to these rats twenty-four hours after reperfusion. The results showed a predominant upregulation of MMP-12 (approximately 47, 58, 143, and 265 folds on days 1, 3, 5, 7 post-ischemia, respectively) in MCAO subjected rats. MMP-12 expression was localized to neurons, oligodendrocytes and microglia, but not astrocytes. Transcriptional inactivation of MMP-12 significantly reduced the infarct size. The percent infarct size was reduced from 62.87 ± 4.13 to 34.67 ± 5.39 after MMP-12 knockdown compared to untreated MCAO subjected rats. Expression of myelin basic protein was increased, and activity of MMP-9 was reduced in ischemic rat brains after MMP-12 knockdown. Furthermore, a significant reduction in the extent of apoptosis was noticed after MMP-12 knockdown. TNFα expression in the ipsilateral regions of MCAO-subjected rats was reduced after MMP-12 knockdown in addition to the reduced protein expression of apoptotic molecules that are downstream to TNFα signaling. Specific knockdown of MMP-12 after focal cerebral ischemia offers neuroprotection that could be mediated via reduced MMP-9 activation and myelin degradation as well as inhibition of apoptosis.