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1 Medicine, William S. Middleton VAMC/University of Wisconsin School of Medicine, Madison, United States
2 Medicine, San Francisco VAMC/University of California School of Medicine, San Francisco, San Francisco, California, United States
3 Medicine and Cardiovascular Research Institute, San Francisco VAMC/University of California School of Medicine, San Francisco, San Francisco, California, United States
* To whom correspondence should be addressed. E-mail: david.lovett{at}med.va.gov.
Matrix metalloproteinase-2 (MMP-2) is central to the to the cardiac injury response. Elevated MMP-2 after ischemia suggests new protein synthesis, but the molecular regulation of MMP-2 druing ischemia/reperfusion (I/R) injury has not been studied. Using the MMP-2 promoter linked to a 
-galactosidase reporter in transgenic mice, we investigated the transcriptional regulation and cellular sources of MMP-2 in isolated, perfused mouse hearts subjected to acute global I/R injury. I/R induced a rapid activation of MMP-2 promoter activity with the appearance of -galactosiase antigen in cardiomyocytes, fibroblasts and endothelial cells. Activation of intrinsic MMP-2 transcription and translation was confirmed by real time PCR and quantitative Western blot analyses. MMP-2 transcription and translation were inhibited by a hydroxyl radical scavenger. Nuclear extracts demonstrated inceased abundance of two AP-1 components, JunB and FosB, following I/R injury. Immunohistochemical staining localized JunB and FosB proteins to the nuclei of all three cardiac cell types following I/R injury, consistent with enhanced nuclear transport of these transcription factors. Chromatin immunoprecipitation (ChIP) of the AP-1 binding site in the intrinsic murine MMP-2 promoter yielded only JunB under control conditions, while ChIP following I/R injury recovered both JunB and FosB, consistent with a change in occupancy from JunB homodimers in controls to JunB/FosB heterodimers following I/R injury. Conclusions: enhanced MMP-2 trasncrition and translation following I/R injury is mediated by induction, via oxidant stress, of discrete AP-1 transcription factor components.
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