TLR2 ligands induce cardioprotection against ischaemia/reperfusion injury through a PI3K/Akt-dependent mechanism.
OBJECTIVE
Toll-like receptor (TLR)-mediated signalling pathways have been implicated in myocardial ischaemia/reperfusion (I/R) injury. Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway protects the myocardium from ischaemic injury. We hypothesized that the modulation of TLR2 would induce cardioprotection against I/R injury via activation of the PI3K/Akt signalling.


RESULTS
Mice were treated with TLR2 ligands, peptidoglycan (PGN) or Pam3CSK4, respectively, 1 h before the hearts were subjected to ischaemia (1 h), followed by reperfusion (4 h). Infarct size was determined by triphenyltetrazolium chloride staining. Cardiac function and haemodynamic performance were evaluated. Infarct size was significantly reduced in PGN- or Pam3CSK4-treated mice compared with untreated I/R mice. Administration of TLR2 ligands improved cardiac function following I/R. PGN treatment increased the levels of phospho-Akt and phospho-GSK-3beta (glycogen synthase kinase-3beta), compared with untreated I/R hearts. PGN stimulation increased TLR2 tyrosine phosphorylation and association of the p85 subunit of PI3K with TLR2. To investigate the role of PI3K/Akt signalling in PGN-induced cardioprotection, we administered the PI3K inhibitor, Wortmannin, to the mice 15 min before PGN treatment. We also administered PGN to kinase-deficient Akt (kdAkt) transgenic mice 1 h before myocardial I/R. Both PI3K inhibition and kdAkt mice abolished the cardioprotection induced by PGN. To examine the role of TLR2 in PGN-induced cardioprotection, we administrated PGN to TLR2 knockout mice 1 h before the hearts were subjected to I/R. PGN-induced cardioprotection was lost in TLR2-deficient mice.


CONCLUSIONS
These results demonstrate that TLR2 ligands induced cardioprotection, which is mediated through a TLR2/PI3K/Akt-dependent mechanism.
Ha
Tuanzhu
T
Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, PO Box 70575, Johnson City, TN 37614-0575, USA.
Hu
Yulong
Y
Liu
Li
L
Lu
Chen
C
McMullen
Julie R
JR
Kelley
Jim
J
Kao
Race L
RL
Williams
David L
DL
Gao
Xiang
X
Li
Chuanfu
C
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006439:Hemodynamics / Q000187:drug effects; D008024:Ligands; D055666:Lipopeptides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D010457:Peptidoglycan / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000172:deficiency / Q000235:genetics; D014443:Tyrosine; D016276:Ventricular Function / Q000187:drug effects
D002316:Cardiotonic Agents; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008024:Ligands; D055666:Lipopeptides; D010457:Peptidoglycan; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051195:Toll-Like Receptor 2; D014443:Tyrosine; C508075:Pam(3)CSK(4) peptide; C493486:Tlr2 protein, mouse; C495343:Tlr2 protein, rat; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat