on March 1, 2007
Published online before print March 1, 2007, doi: 10.1161/ATVBAHA.107.140723
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Submitted on April 7, 2006
Accepted on February 19, 2007
Toll-Like Receptors 2-Deficient Mice Are Protected Against Postischemic Coronary Endothelial Dysfunction
Julie Favre ;
From the Inserm U644 & Rouen University Hospital (J.F., K.L., J.-P.H., C.T., V.R.) and Inserm U519 (P.M.), Institute for Biomedical Research and IFRMP 23, University of Rouen, France; and Inserm U868 (V.D.-E., J.-F.A.), Toulouse France.
* To whom correspondence should be addressed. E-mail: Vincent.Richard{at}univ-rouen.fr.
Objectives--Toll-like receptors (TLR) 2 are expressed in cardiac and inflammatory cells, and regulate leukocyte function. Because leukocyte adhesion is a critical event in endothelial injury induced by ischemia/reperfusion (I/R), we assessed whether TLR2 were involved in I/R - induced coronary endothelial injury.
Methods and Results--Ischemia - reperfusion markedly decreased NO-mediated coronary relaxations to acetylcholine assessed ex vivo. In contrast, in TLR2 deficient mice, I/R paradoxically improved the NO-mediated responses to acetylcholine. To precise the cellular compartment expressing TLR2 which is involved in endothelial injury, we developed bone-marrow chimeric mice by transplanting TLR2-/- bone marrow to WT mice or WT bone marrow to TLR2-/- mice and submitted them to I/R 5 weeks after transplant. Both chimeric mice displayed similar protection as TLR2-/- mice against I/R-induced endothelial dysfunction, suggesting a role of TLR2 expressed on both non-bone marrow cells (in our case presumably endothelial cells and/or cardiomyocytes) and cells of bone marrow origin (presumably neutrophils). TLR2 deficiency was also associated with a smaller infarct size, and reduced reperfusion-induced production of reactive oxygen species and leukocyte infiltration.
Conclusions--TLR2 contribute to coronary endothelial dysfunction after I/R, possibly through stimulation of neutrophil- (and free radical-) mediated endothelial injury.
Key words: endothelium • nitric oxide • ischemia • leukocytes • immune system
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