Modulation of TLR2 induces cardioprotection through a Phosphoinositide 3‐Kinase Dependent Mechanism

Abstract

We have reported that the immune modulator, glucan, rapidly induces cardioprotection. TLR2 is required for glucan activation of cellular signaling. However, the role of TLR2 in cardioprotection has not been investigated. Peptidoglycan (PDG) activates cellular signaling specifically through TLR2. In this study we examined the effect of modulation of TLR2 on myocardial I/R injury. TLR2 KO (n=8) and wild type mice (n=8) were treated with PDG (100 ƒÝg/25g) or glucan (1 mg/25g) one hr before the hearts were subjected to ischemia (1 hr)/reperfusion (4 hrs). Untreated mice (n=8) served as control. To investigate the role of PI3K/Akt in modulation of TLR2-induced cardioprotection, we administered PDG (100 ƒÝg/25g) or glucan (1 mg/25g) to kdAkt transgenic mice (n=8) one hr before I/R. Myocardial infarction was determined by TTC staining. Infarct size was significantly reduced in PDG (10.5 ¡Ó 3.03% vs 30.1 ¡Ó 7.59%, p<0.01) and glucan (11.6 ¡Ó 2.38% vs 36.1 ¡Ó 3.48%, p<0.01) treated mice vs untreated mice. Both PDG and glucan-induced cardioprotection were completely abolished in TLR2 KO mice. The cardioprotection induced by either direct (PDG) or indicate (glucan) modulation of TLR2 was also abolished in kdAkt mice. The results suggest that the mechanism of modulation of TLR2-induced cardioprotection is mediated through a PI3K/Akt dependent mechanism and that there is a link between TLR2 and PI3K/Akt signaling during I/R.