Toll-like receptor 4 modulates myocardial ischaemia-reperfusion injury: Role of matrix metalloproteinases.
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.
Stapel
Heidi
H
Institute of Physiology II, University of Bonn, Germany.
Kim
Se-Chan
SC
Osterkamp
Steffen
S
Knuefermann
Pascal
P
Hoeft
Andreas
A
Meyer
Rainer
R
Grohé
Christian
C
Baumgarten
Georg
G
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*
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D051197:Toll-Like Receptor 4; D020782:Matrix Metalloproteinases