Abstract 169: Activation of the Phosphoinositide 3-Kinase/Akt Pathway is Responsible for Cardioprotection Induced by Modulation of TLR2
Activation of the phosphoinositide-3 kinase/Akt (PI3K/Akt) signaling pathway protects cells from ischemic injury. We have reported that the immune modulator, glucan, rapidly induces cardioprotection. Dectin-1 is a specific receptor for glucan and Toll-like receptor 2 (TLR2) is required for transmitting the signal from Dectin-1 into cells. However, the role of modulation of TLR2 in cardioprotection has not been investigated. We hypothesized that modulation of TLR2 will induce cardioprotection through a PI3K/Akt-dependent mechanism. To evaluate our hypothesis, we examined the effect of modulation of TLR2 on myocardial ischemic injury. TLR2 knockout (KO) (n=8) and wild type mice (n=8) were treated with glucan (1 mg/25g) or peptidoglycan (PDG, 75 μg/25g), a specific TLR2 ligand, one hr before the hearts were subjected to ischemia (1 hr)/reperfusion (4 hrs). Untreated mice (n=8) were also subjected to I/R. Myocardial infarction was determined by TTC staining. Infarct size was significantly reduced in glucan (11.6 ± 2.38% vs 36.1 ± 3.48%, p<0.01) and PDG (10.5 ± 3.03% vs 30.1 ± 7.59%, p<0.01) treated mice vs untreated mice. The levels of phospho-Akt (0.80 ± 0.10 vs 0.45 ± 0.09) and phospho-GSK3β (0.66 ± 0.14 vs 0.33 ± 0.10) were significantly increased in the myocardium of glucan treated mice compared with untreated mice. However, both glucan and PDG-induced cardioprotection were completely abolished in TLR2 KO mice. To investigate whether PI3K/Akt signaling is involved in cardioprotection induced by modulation of TLR2, we administered glucan (1 mg/25g) or PDG (75 μg/25g) to kdAkt (kinase deficient Akt) transgenic mice (n=8) one hr before myocardial I/R. Both glucan and PDG-induced cardioprotection were completely abolished in kdAkt mice. The results suggest that modulation of TLR2, either directly or indirectly, will induce cardioprotection through a PI3K/Akt dependent mechanism and that there is a critical link between TLR2 and PI3K/Akt signaling during myocardial I/R.