title: Toll-like receptor 4 modulates myocardial ischaemia-reperfusion injury: Role of matrix metalloproteinases.
abstract: Toll-like receptor 4 (TLR4) mediates innate immune responses following endotoxemia and myocardial ischaemia-reperfusion (I/R) injury. Pre-treatment with the major TLR4 ligand lipopolysaccharide (LPS) reduces infarct size. Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play a crucial role in endotoxemia possibly also determining I/R injury.
  
  
  OBJECTIVE
  We investigated the influence of TLR4 on infarct size and assessed the influence of MMP and TIMP regulation on I/R injury.
  
  
  METHODS
  Left anterior descending artery (LAD) occlusion was performed on wild-type (C3H/HeN) and TLR4-deficient (C3H/HeJ) mice. Animals were stimulated with LPS (1 mg/kg) or PBS 16 h ahead of 60 min LAD ligation. After 24 h of reperfusion, triphenyltetrazolium chloride staining was performed and infarct size was measured by planimetry. MMP- and TIMP-mRNA expression were determined by RPA after 3 h of reperfusion. MMP zymographic activity was monitored 6 h after occlusion.
  
  
  RESULTS
  TLR4-deficient mice and LPS-treated wild-type mice showed significantly reduced infarct areas. LPS-stimulation significantly increased the overall MMP/TIMP mRNA expression ratio due to elevated MMP-3, -8, -9, and TIMP-1 in wild-type mice. I/R overall reduced the MMP/TIMP ratio due to increased MMP-1, TIMP-1, and -3 mRNA expression.
  
  
  CONCLUSIONS
  LPS pre-treatment and TLR4-deficiency led to a decreased infarct size. However, infarct area and MMP/TIMP ratio were not correlated. This means that in TLR4-deficient mice MMP/TIMP ratios are not determining the infarct size.
authors.affiliation: Institute of Physiology II, University of Bonn, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Stapel
authors.forename: Se-Chan
authors.initials: SC
authors.lastname: Kim
authors.forename: Steffen
authors.initials: S
authors.lastname: Osterkamp
authors.forename: Pascal
authors.initials: P
authors.lastname: Knuefermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeft
authors.forename: Rainer
authors.initials: R
authors.lastname: Meyer
authors.forename: Christian
authors.initials: C
authors.lastname: Grohé
authors.forename: Georg
authors.initials: G
authors.lastname: Baumgarten
mesh_terms: D000818:Animals; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009203:Myocardial Infarction / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D051197:Toll-Like Receptor 4; D020782:Matrix Metalloproteinases