Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways

• Published in: American journal of physiology. Heart and circulatory physiology 2010-03, Vol.298 (3), p.H1079-H1087
• Main Authors: Dong, Jian-Wen, Vallejo, Jesus G, Tzeng, Huei-Ping, Thomas, James A, Mann, Douglas L
• Format: Article
• Language: English
• Subjects: Animals; Brain damage; Disease Models, Animal; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Heart attacks; Immunity, Innate - physiology; Ischemia; Ischemic Preconditioning, Myocardial; Kinases; Lipopeptides - therapeutic use; Liver; Male; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myocardial Reperfusion Injury - complications; Myocardial Reperfusion Injury - physiopathology; Physiology; Protein Kinase C-epsilon - metabolism; Proteins; Receptors, Interleukin-1 - deficiency; Receptors, Interleukin-1 - physiology; Rodents; Signal Transduction - physiology; Toll-Like Receptor 2 - deficiency; Toll-Like Receptor 2 - physiology; Toll-Like Receptor 4 - deficiency; Toll-Like Receptor 4 - physiology; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - prevention & control
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00306.2009

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.