Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways.
Recent studies have implicated Toll-like receptor 2 (TLR2) and TLR4 signaling in delimiting liver and brain injury following ischemia-reperfusion (I/R). To determine whether TLR2 and TLR4 conferred cytoprotection in the heart, we subjected hearts of wild-type (WT) mice and mice deficient in TLR2 (TLR2D), TLR4 (TLR4D), and TIR domain-containing adapter protein (TIRAP-D) to ischemic preconditioning (IPC). Langendorff-perfused hearts were subjected to 30 min ischemia and 60 min reperfusion with or without IPC. IPC resulted in a significant increase (P < 0.05) in the percent recovery of left ventricular developed pressure (%LVDP) in WT mouse hearts (54.4 +/- 2.7% of baseline), whereas there was no significant increase in %LVDP (P > 0.05) in TIRAP-D mouse hearts (43.8 +/- 1.9%) after I/R injury. IPC also resulted in a significant (P < 0.05) decrease in I/R-induced creatine kinase release and Evans blue dye uptake in WT but not TIRAP-D hearts. Interestingly, IPC resulted in a significant (P < 0.05) increase in %LVDP in TLR4-deficient hearts (52.7 +/- 3%) but not in TLR2D hearts (39.3 +/- 1.5%). Pretreatment with a specific TLR2 ligand (Pam3CSK) protected WT hearts against I/R-induced left ventricular dysfunction. The loss of IPC-induced cardioprotection in TIRAP-D mouse hearts was accompanied by a decreased translocation of protein kinase C-epsilon and decreased phosphorylation of GSK-3beta. Taken together, these data suggest that the cardioprotective effect of IPC is mediated, at least in part, through a TLR2-TIRAP-dependent pathway, suggesting that the modulation of this pathway represents a viable target for reducing I/R injury.
Dong
Jian-Wen
JW
Department of Medicine, Winters Center for Heart Failure Research, Baylor College of Medicine and Texas Children's Hospital, Houston, USA.
Vallejo
Jesus G
JG
Tzeng
Huei-Ping
HP
Thomas
James A
JA
Mann
Douglas L
DL
D000818:Animals; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007113:Immunity, Innate / Q000502:physiology*; D019157:Ischemic Preconditioning, Myocardial; D055666:Lipopeptides / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000503:physiopathology*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000517:prevention & control
D055666:Lipopeptides; D008562:Membrane Glycoproteins; C508075:Pam(3)CSK(4) peptide; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051744:Protein Kinase C-epsilon; D038362:Glycogen Synthase Kinase 3