Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism
Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism
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DOI：
10.1093/cvr/cvn037
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发表时间：
2008-06-01
影响因子：
10.8
通讯作者：
Li, Chuanfu
中科院分区：
文献类型：
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作者：
Ha, Tuanzhu;Hua, Fang;Li, Chuanfu
施舍 脂多糖 (LPS) 预处理诱导缺血/再灌注 (I/R) 后心脏保护的能力已得到充分证明。然而，其机制尚未完全阐明。 LPS 是一种 Toll 样受体 4 (TLR4) 配体。最近的证据表明 TLR 和磷酸肌醇 3-激酶/Akt (PI3K/Akt) 信号通路之间存在串扰。我们假设 PI3K/Akt 信号传导的激活在 LPS 诱导的心脏保护中发挥关键作用。 方法和结果 为了评估这一假设，我们在心脏缺血（45 分钟）和再灌注（4 小时）前 24 小时用 LPS 预处理小鼠。我们检查了 PI3K/Akt/GSK-3 β 信号通路的激活。还评估了 PI3K/Akt 抑制对 LPS 诱导的心脏保护作用的影响。与未治疗组相比，LPS 预处理显着减少了梗塞面积 (71.25%)（9.3 +/- 1.58 vs. 32.3 +/- 2.92%，P < 0.01）。 I/R 后，LPS 预处理小鼠的心肌细胞凋亡和 caspase-3 活性显着降低。 LPS 预处理显着增加了心肌中磷酸-Akt、磷酸-GSK-3β 和热休克蛋白 27 的水平。 LY294002 对 PI3K 的药理抑制或使用激酶缺陷型 Akt 转基因小鼠的基因调节消除了 LPS 诱导的心脏保护作用。结论这些结果表明 I/R 损伤中 LPS 诱导的心脏保护作用是通过 PI3K/Akt 依赖性机制介导的。
Alms The ability of lipopolysaccharide (LPS) pre-treatment to induce cardioprotection following ischaemia/reperfusion (I/R) has been well documented; however, the mechanisms have not been fully elucidated. LPS is a Toll-like receptor 4 (TLR4) ligand. Recent evidence indicates that there is cross-talk between the TLR and phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathways. We hypothesized that activation of PI3K/Akt signalling plays a critical role in LPS-induced cardioprotection.Methods and results To evaluate this hypothesis, we pre-treated mice with LPS 24 h before the hearts were subjected to ischaemia (45 min) and reperfusion (4 h). We examined activation of the PI3K/Akt/GSK-3 beta signalling pathway. The effect of PI3K/Akt inhibition on LPS-induced cardioprotection was also evaluated. LPS pre-treatment significantly reduced infarct size (71.25%) compared with the untreated group (9.3 +/- 1.58 vs. 32.3 +/- 2.92%, P < 0.01). Cardiac myocyte apoptosis and caspase-3 activity in LPS-pre-treated mice were significantly reduced following I/R. LPS pre-treatment significantly increased the levels of phospho-Akt, phospho-GSK-3 beta, and heat shock protein 27 in the myocardium. Pharmacological inhibition of PI3K by LY294002 or genetic modulation employing kinase-defective Akt transgenic mice abolished the cardioprotection induced by LPS.Conclusion These results indicate that LPS-induced cardioprotection in I/R injury is mediated through a PI3K/Akt-dependent mechanism.