© 2006 European Society of Cardiology
Toll-like receptor 4 modulates myocardial ischaemia–reperfusion injury: Role of matrix metalloproteinases
a Institute of Physiology II, University of Bonn, Germany
b Department of Anaesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany
c Medizinische Universitätspoliklinik, University of Bonn, Germany
* Corresponding author. Tel.: +49 228 287 4124; fax: +49 228 287 4115. E-mail address: Georg.Baumgarten{at}ukb.uni-bonn.de (G. Baumgarten).
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Abstract |
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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.
Aims: 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 (1mg/kg) or PBS 16h ahead of 60min LAD ligation. After 24h of reperfusion, triphenyltetrazolium chloride staining was performed and infarct size was measured by planimetry. MMP- and TIMP-mRNA expression were determined by RPA after 3h of reperfusion. MMP zymographic activity was monitored 6h 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.
Key Words: TLR4 • MMP/TIMP • Myocardial ischemia–reperfusion • Ligand lipopolysaccharide
Received June 22, 2005; Revised December 16, 2005; Accepted March 16, 2006
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