Protection against myocardial ischemia/reperfusion injury by differential modulation of TLR2 and TLR4

【Author】

KELLEY Jim;BROWDER I.William;KAO Race L;WILLIAMS David L;

【Abstract】

<正>Innate immune and inflammatory responses are implicated in myocardial ischemic injury.However,the mechanisms are unknown.Toll-like receptors play a critical role in the induction of innate immune and inflammatory responses.Recent studies have shown that Toll-like receptor 2(TLR2) and TLR4 play an important role in myocardial ischemia/reperfusion(I/R) injury.However,the effects of differential modulation of TLR2 and TLR4 on myocardial ischemic injury have not been investigated entirely.In the present study,we examined whether modulation of TLR2 and TLR4 by their specific ligand will induce protection against myocardial ischemia/reperfusion injury.Peptidoglycan(PDG,75μg/25 g),a specific ligand of TLR2 was administered to experimental mice(n=8) 1 h before the hearts were subjected to ischemia(1 h)/reperfusion(4 h).Lipopolysaccharide(LPS,0.2 mg/kg),a specific ligand of TLR4,was given to the mice(n=8) 24 h before myocardial I/R.Untreated mice(n=8) were also subjected to I/R.Myocardial infarction was determined by TIC staining.PDG administration significantly reduced infarct size[(10.5±3.03)%]compared with untreated mice[(30.1±7.59)%,P<0.01].Pretreatment of mice with LPS for 24 h also significantly reduced infarct size by 66.5%compared to untreated controls[(11.7±1.45)%vs (34.9±5.39)%,P<0.01].Importantly,PDG administration significantly increased 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) in the myocardium compared with untreated I/R mice.Similarly,LPS pretreatment also significantly increased the levels of phospho-Akt and phospho-GSK -3βin the myocardium.Pharmacological inhibition of PI3K by LY294002 or genetic modulation employing kinase defective Akt(kdAkt) transgenic mice abolished the cardioprotection induced by either PDG or by LPS.The data suggest that TLR2 agonist(PDG)-mediated protection against I/R injury does not require prolonged pretreatment while TLR4 agonist LPS requires 24 h of pretreatment to induce a tolerogenic phenotype in the heart.The results suggest that modulation of TLR2,or TLR4 will induce cardioprotection through a PI3K/Akt-dependent signaling pathway although the mechanisms by which TLR2 or TLR4 ligand-induced activation of the PI3K/Akt signaling pathway may be different.

【Keywords】

Toll-like receptors;;myocardial ischemia/reperfusion injury;;PI3K/Akt signaling pathway

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