A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity.
A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity.
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DOI：
10.1371/journal.pone.0034177
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Karliner JS
中科院分区：
文献类型：
--
作者：
Lovett DH;Mahimkar R;Raffai RL;Cape L;Maklashina E;Cecchini G;Karliner JS
实验和临床证据已经明确了基质金属蛋白酶-2（MMP-2）在缺血性心室重构和收缩性心力衰竭中的关键作用。先前的研究已经证明，全长68 kDa分泌型MMP-2的转基因表达诱导严重的收缩功能衰竭。这些小鼠还具有意想不到的和严重的线粒体结构异常和功能障碍。我们假设，一个额外的细胞内的MMP-2亚型，影响线粒体功能的收缩功能衰竭相关的氧化应激条件下诱导。来自全长MMP-2转基因小鼠、老龄小鼠和加速动脉粥样硬化模型的心脏线粒体的蛋白质印迹显示较小的65 kDa MMP-2亚型。培养的心肌细胞进行短暂的氧化应激产生的65 kDa的MMP-2亚型。65 kDa的MMP-2亚型也诱导心肌细胞缺氧培养。MMP-2基因的基因组数据库分析绘制了MMP-2基因第一内含子内缺氧或表观遗传修饰剂诱导的转录起始位点和RNA转录物。这些转录本的翻译产生65 kDa的N-末端截短的亚型开始于M77，从而删除信号序列和抑制性前结构域。细胞运输研究表明，65 kDa的MMP-2亚型不分泌，并存在于胞质和线粒体组分，而全长68 kDa的亚型被发现只在细胞外空间。65 kDa MMP-2亚型的表达诱导了细胞核应激信号传导，并激活了促炎性NF-κB、NFAT和IRF转录途径。通过微阵列，65 kDa MMP-2诱导先天免疫转录组，包括病毒应激反应基因，先天免疫转录因子IRF 7，趋化因子和促凋亡基因。一种新的N-末端截短的细胞内MMP-2亚型是由氧化应激诱导的。这种同种型启动原发性先天免疫应答，其可能在缺血和收缩衰竭的情况下导致进行性心功能障碍。
Experimental and clinical evidence has pinpointed a critical role for matrix metalloproteinase-2 (MMP-2) in ischemic ventricular remodeling and systolic heart failure. Prior studies have demonstrated that transgenic expression of the full-length, 68 kDa, secreted form of MMP-2 induces severe systolic failure. These mice also had unexpected and severe mitochondrial structural abnormalities and dysfunction. We hypothesized that an additional intracellular isoform of MMP-2, which affects mitochondrial function is induced under conditions of systolic failure-associated oxidative stress. Western blots of cardiac mitochondria from the full length MMP-2 transgenics, ageing mice and a model of accelerated atherogenesis revealed a smaller 65 kDa MMP-2 isoform. Cultured cardiomyoblasts subjected to transient oxidative stress generated the 65 kDa MMP-2 isoform. The 65 kDa MMP-2 isoform was also induced by hypoxic culture of cardiomyoblasts. Genomic database analysis of the MMP-2 gene mapped transcriptional start sites and RNA transcripts induced by hypoxia or epigenetic modifiers within the first intron of the MMP-2 gene. Translation of these transcripts yields a 65 kDa N-terminal truncated isoform beginning at M77, thereby deleting the signal sequence and inhibitory prodomain. Cellular trafficking studies demonstrated that the 65 kDa MMP-2 isoform is not secreted and is present in cytosolic and mitochondrial fractions, while the full length 68 kDa isoform was found only in the extracellular space. Expression of the 65 kDa MMP-2 isoform induced mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-κB, NFAT and IRF transcriptional pathways. By microarray, the 65 kDa MMP-2 induces an innate immunity transcriptome, including viral stress response genes, innate immunity transcription factor IRF7, chemokines and pro-apoptosis genes. A novel N-terminal truncated intracellular isoform of MMP-2 is induced by oxidative stress. This isoform initiates a primary innate immune response that may contribute to progressive cardiac dysfunction in the setting of ischemia and systolic failure.
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影响因子：
37.8
作者：
Ali MA;Cho WJ;Hudson B;Kassiri Z;Granzier H;Schulz R
通讯作者：
Schulz R
DOI：
10.1152/ajpheart.00207.2003
发表时间：
2003-09-01
影响因子：
4.8
作者：
Hayashidani, S;Tsutsui, H;Takeshita, A
通讯作者：
Takeshita, A
DOI：
10.1073/pnas.0508085102
发表时间：
2005-11-08
影响因子：
11.1
作者：
Lee, JG;Dahi, S;Sarkar, R
通讯作者：
Sarkar, R
影响因子：
2.9
作者：
BERGMANN, U;TUUTTILA, A;TRYGGVASON, K
通讯作者：
TRYGGVASON, K
DOI：
10.1083/jcb.200211104
发表时间：
2003-05-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Biswas G;Anandatheerthavarada HK;Zaidi M;Avadhani NG
通讯作者：
Avadhani NG