Abstract
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.
Highlights
We recently reported on the detailed characterization of an N-terminal truncated intracellular isoform of Matrix metalloproteinase-2 (MMP-2) (NTTMMP-2) generated by oxidative stress-mediated activation of an alternative promoter in the first intron of the MMP-2 gene [1]
We further demonstrated that the NTTMMP-2 isoform initiated mitochondrial-nuclear stress signaling via activation of Nuclear Factor of Activated T-cells (NFAT), NF-κB and Interferon Response Factor-7 (IRF-7) transcriptional networks
In order to determine the pathophysiologic significance of the N-terminal truncated MMP-2 protein within the context of the intact heart, we generated cardiac-specific transgenic mice as detailed in Materials and Methods
Summary
We recently reported on the detailed characterization of an N-terminal truncated intracellular isoform of MMP-2 (NTTMMP-2) generated by oxidative stress-mediated activation of an alternative promoter in the first intron of the MMP-2 gene [1]. The 65 kDa MMP-2 isoform was initially detected in mitochondria-enriched preparations from aging wild type mice and in mitochondrial preparations of hypomorphic ApoE mice expressing an ApoE-like form of mouse ApoE ( referred to as “HypoE” mice). These mice are deficient in the SF-B1 receptor (ApoER61h/h/SR-B1−/− mice) and represent a model of diet-induced coronary atherosclerosis and myocardial infarction [1,3]. The NTT-MMP-2 isoform was detected within mitochondrial preparations from cardiac-specific transgenic mice expressing the full length, secreted 68 kDa constitutively active isoform of MMP-2 in the setting of advanced ventricular systolic failure [1,4]
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