N-terminal truncated intracellular matrix metalloproteinase-2 induces cardiomyocyte hypertrophy, inflammation and systolic heart failure.
N-terminal truncated intracellular matrix metalloproteinase-2 induces cardiomyocyte hypertrophy, inflammation and systolic heart failure.
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DOI：
10.1371/journal.pone.0068154
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发表时间：
2013
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;Zhu BQ;Jin ZQ;Baker AJ;Karliner JS
基质金属蛋白酶-2(MMP2)在心肌缺血再灌注损伤和缺血性心肌重塑中起重要作用。这些情况的一个共同特征是氧化应激增加，这一过程涉及多个促炎和先天免疫级联反应。我们最近报道了通过氧化应激激活位于基质金属蛋白酶-2基因第一内含子内的替代启动子而产生的一种胞内异构体的基质金属蛋白酶-2。从这个位置转录产生一个N端截短的65 kDa的基质金属蛋白酶-2亚型(NTT-基质金属蛋白酶-2)，它缺乏分泌序列和抑制原结构域。NTT-MMP2亚型是细胞内的，具有酶活性，部分定位于线粒体。Ntt-MMP2亚型的表达触发了活化T细胞的核因子和NF-κB信号，并伴随着高度定义的天然免疫转录组的表达，包括白介素6、单核细胞趋化蛋白-1、IRF-7和促凋亡转录本。为了确定NTT-MMP2亚型在体内的功能意义，我们建立了心脏特异的NTT-MMP2转基因小鼠。这些小鼠发展为进行性心肌细胞肥大和与收缩性心力衰竭相关的心室肥厚。此外，有证据表明心肌细胞凋亡和心肌单核细胞浸润。NTT-MMP2转基因心脏在体外缺血再灌注损伤后也表现出更严重的损伤。我们得出结论，在没有叠加损伤的情况下，氧化应激诱导的一种新的细胞内基质金属蛋白酶-2亚型直接导致心肌细胞肥大。炎症、收缩性心力衰竭和对缺血-再灌注损伤的易感性增加。
Matrix metalloproteinase-2 (MMP-2) is increasingly recognized as a major contributor to progressive cardiac injury within the setting of ischemia-reperfusion injury and ischemic ventricular remodeling. A common feature of these conditions is an increase in oxidative stress, a process that engages multiple pro-inflammatory and innate immunity cascades. We recently reported on the identification and characterization of an intracellular isoform of MMP-2 generated by oxidative stress-mediated activation of an alternative promoter located within the first intron of the MMP-2 gene. Transcription from this site generates an N-terminal truncated 65 kDa isoform of MMP-2 (NTT-MMP-2) that lacks the secretory sequence and the inhibitory prodomain region. The NTT-MMP-2 isoform is intracellular, enzymatically active and localizes in part to mitochondria. Expression of the NTT-MMP-2 isoform triggers Nuclear Factor of Activated T-cell (NFAT) and NF-κB signaling with the expression of a highly defined innate immunity transcriptome, including Interleukin-6, MCP-1, IRF-7 and pro-apoptotic transcripts. To determine the functional significance of the NTT-MMP-2 isoform in vivo we generated cardiac-specific NTT-MMP-2 transgenic mice. These mice developed progressive cardiomyocyte and ventricular hypertrophy associated with systolic heart failure. Further, there was evidence for cardiomyocyte apoptosis and myocardial infiltration with mononuclear cells. The NTT-MMP-2 transgenic hearts also demonstrated more severe injury following ex vivo ischemia-reperfusion injury. We conclude that a novel intracellular MMP-2 isoform induced by oxidant stress directly contributes, in the absence of superimposed injury, to cardiomyocyte hypertrophy. inflammation, systolic heart failure and enhanced susceptibility to ischemia-reperfusion injury.
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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
影响因子：
2.9
作者：
BERGMANN, U;TUUTTILA, A;TRYGGVASON, K
通讯作者：
TRYGGVASON, K
影响因子：
4.6
作者：
Arbustini, Eloisa;Brega, Agnese;Narula, Jagat
通讯作者：
Narula, Jagat
影响因子：
3.5
作者：
Rizzi, Elen;Castro, Michele M.;Gerlach, Raquel F.
通讯作者：
Gerlach, Raquel F.
影响因子：
20.1
作者：
Liu Q;Chen Y;Auger-Messier M;Molkentin JD
通讯作者：
Molkentin JD