title: N-terminal truncated intracellular matrix metalloproteinase-2 induces cardiomyocyte hypertrophy, inflammation and systolic heart failure.
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.
authors.affiliation: Department of Medicine, San Francisco Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, California, United States of America. david.lovett@va.gov
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
authors.forename: Rajeev
authors.initials: R
authors.lastname: Mahimkar
authors.forename: Robert L
authors.initials: RL
authors.lastname: Raffai
authors.forename: Leslie
authors.initials: L
authors.lastname: Cape
authors.forename: Bo-Qing
authors.initials: BQ
authors.lastname: Zhu
authors.forename: Zhu-Qiu
authors.initials: ZQ
authors.lastname: Jin
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baker
authors.forename: Joel S
authors.initials: JS
authors.lastname: Karliner
mesh_terms: D000818:Animals; D054143:Heart Failure, Systolic / Q000201:enzymology* / Q000235:genetics; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000473:pathology*; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D050839:Interferon Regulatory Factor-7; D015850:Interleukin-6; D020033:Protein Isoforms; D020778:Matrix Metalloproteinase 2