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COX-2 IN MYOCARDIAL INJURY AND REMODELLING: ELUCIDATING MECHANISMS OF INDUCTION BY FIBRONECTIN FRAGMENTS INCLUDING EXTRA-DOMAIN A
  1. V Freixa1,2,*,
  2. M A Paul2,
  3. A Francois2,
  4. V Budhram-Mahadeo3,
  5. R J Heads2
  1. 1Universitat Pompeu Fabra, Barcelona, Spain
  2. 2King's College London, Cardiovascular Division, BHF Center for Research Excellence, London, UK
  3. 3Medical Molecular Biology Unit, Institute of Child Health, University College London, UK

    Abstract

    Cyclooxygenases (COXs) catalyse the rate-limiting step in prostanoid synthesis. COX-2 is essential for cardiovascular homeostasis and cardioprotection. Myocardial COX-2 induction occurs in the interstitial myofibroblast (MF) compartment via two distinct mechanisms: G-protein coupled receptor (GPCR) and Toll-like receptor (TLR) activation. The aim was to identify the mechanism of GPCR/TLR induced COX-2 expression and to establish a paradigm for a broader gene regulatory network (GRN) associated with positive remodelling. We demonstrate that of the Galpha(q)-coupled GPCR agonists tested, only Angiotensin-II (AngII) induced COX-2 showing a peak in protein expression at 4 h, suggesting a mechanisms unique to AngII. The TLR agonists Lipopolysaccharide (LPS) and extracellular matrix (ECM) components, such as the Extra Domain A (EDA) and C-terminal region of the first type III repeat (III1-C) of Fibronectin (FN), bind to TLR4 and stimulate sustained COX-2 expression (>24 h). Reporter assays in HEK-293 cells show that the TLR4/MD2/CD14 receptor/co-receptor complex was required for LPS signals, whereas FN-EDA only required TLR4/MD2. Moreover, protein kinase C (PKC)epsilon and calcineurin, but not NFκB, mediate COX-2 induction by FN-EDA and AngII and TLR4-dependent COX-2 induction was potentiated by AngII. Gene expression profiling of MFs co-transfected with active calcineurin and PKCepsilon using Affymetrix arrays and Q-RT-PCR show COX-2 is an expression marker of a wound healing phenotype associated with downregulation of fibrosis markers. Therefore, COX-2 induction by TLR4 and ECM-derived damage-associated molecular patterns (DAMPs), including FN-EDA, could play a protective role in myocardial remodelling after events such as ischaemia/reperfusion which disrupt the ECM and release ECM protein fragments.

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