Cardiac ischemia-reperfusion injury induces matrix metalloproteinase-2 expression through the AP-1 components FosB and JunB
Open Access
- 1 October 2006
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 291 (4), H1838-H1846
- https://doi.org/10.1152/ajpheart.00026.2006
Abstract
Matrix metalloproteinase-2 (MMP-2) is a central component of the response to injury in the heart. During ischemia, MMP-2 influences ventricular performance and is a determinant of postinfarction remodeling. Elevation of MMP-2 during reperfusion after ischemia suggests that new protein is synthesized, but the molecular regulation of MMP-2 generation during ischemia-reperfusion (I/R) injury has not been studied. Using the MMP-2 promoter linked to a β-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 injury induced a rapid activation of MMP-2 promoter activity with the appearance of β-galactosidase 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 perfusion with 1.0 mM hydroxyl radical scavenger N-(-2-mercaptopropionyl)-glycine. Nuclear extracts demonstrated increased abundance of two activator proteins-1 (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, whereas 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. We conclude that enhanced MMP-2 transcription and translation following I/R injury are mediated by induction, via oxidant stress, of discrete AP-1 transcription factor components.Keywords
This publication has 40 references indexed in Scilit:
- Co-operative interactions between NFAT (nuclear factor of activated T cells) c1 and the zinc finger transcription factors Sp1/Sp3 and Egr-1 regulate MT1-MMP (membrane type 1 matrix metalloproteinase) transcription by glomerular mesangial cellsBiochemical Journal, 2004
- Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-αAmerican Journal of Physiology-Cell Physiology, 2004
- Activation Systems for Latent Matrix Metalloproteinase-2 are Upregulated Immediately after Focal Cerebral IschemiaJournal of Cerebral Blood Flow & Metabolism, 2003
- A functional activating protein 1 (AP-1) site regulates matrix metalloproteinase 2 (MMP-2) transcription by cardiac cells through interactions with JunB-Fra1 and JunB-FosB heterodimersBiochemical Journal, 2003
- Integration of concepts: Cardiac extracellular matrix remodeling after myocardial infarctionJournal of Cardiac Failure, 2002
- Tumour metastasis suppressor, nm23-β, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1)Biochemical Journal, 2002
- Oxygen radicals trigger activation of NF-κB and AP-1 and upregulation of ICAM-1 in reperfused canine heartAmerican Journal of Physiology-Heart and Circulatory Physiology, 2002
- Matrix Metalloproteinase-2 Contributes to Ischemia-Reperfusion Injury in the HeartCirculation, 2000
- Matrix metalloproteinase synthesis and expression in isolated LV myocyte preparationsAmerican Journal of Physiology-Heart and Circulatory Physiology, 1999
- Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nucleiNucleic Acids Research, 1983