TLR2 ligands induce cardioprotection against ischaemia/reperfusion injury through a PI3K/Akt-dependent mechanism
TLR2 ligands induce cardioprotection against ischaemia/reperfusion injury through a PI3K/Akt-dependent mechanism
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DOI：
10.1093/cvr/cvq116
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发表时间：
2010-09-01
影响因子：
10.8
通讯作者：
Li, Chuanfu
中科院分区：
文献类型：
--
作者：
Ha, Tuanzhu;Hu, Yulong;Li, Chuanfu
Toll样受体（TLR）介导的信号通路参与心肌缺血/再灌注（I/R）损伤。磷酸肌醇3-激酶（PI 3 K）/Akt通路的激活保护心肌免受缺血性损伤。我们假设TLR 2的调节可能通过激活PI 3 K/Akt信号通路诱导心肌保护作用，在心肌缺血前1h（1h），分别用TLR 2配体肽聚糖（PGN）或Pam 3CSK 4处理小鼠，然后再灌注（4 h）。通过氯化三苯基四氮唑染色测定细胞大小。评价心功能和血流动力学性能。与未处理的I/R小鼠相比，PGN或Pam 3CSK 4处理的小鼠的脑体积显著减小。TLR 2配体的给药改善了I/R后的心功能。与未经治疗的I/R心脏相比，PGN治疗增加了磷酸化Akt和磷酸化GSK-3 β（糖原合成酶激酶-3 β）的水平。PGN刺激增加TLR 2酪氨酸磷酸化和PI 3 K的p85亚基与TLR 2的关联。为了研究PI 3 K/Akt信号传导在PGN诱导的心脏保护中的作用，我们在PGN治疗前15分钟向小鼠施用PI 3 K抑制剂Wortmannin。在心肌I/R前1小时，我们还将PGN给予激酶缺陷型Akt（kdAkt）转基因小鼠。PI 3 K抑制和kdAkt小鼠均取消了PGN诱导的心脏保护作用。为了研究TLR 2在PGN诱导的心脏保护中的作用，我们在心脏经受I/R之前1小时向TLR 2敲除小鼠施用PGN。这些结果表明，TLR 2配体诱导的心脏保护作用是通过TLR 2/PI 3 K/Akt依赖性机制介导的。
Toll-like receptor (TLR)-mediated signalling pathways have been implicated in myocardial ischaemia/reperfusion (I/R) injury. Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway protects the myocardium from ischaemic injury. We hypothesized that the modulation of TLR2 would induce cardioprotection against I/R injury via activation of the PI3K/Akt signalling.Mice were treated with TLR2 ligands, peptidoglycan (PGN) or Pam3CSK4, respectively, 1 h before the hearts were subjected to ischaemia (1 h), followed by reperfusion (4 h). Infarct size was determined by triphenyltetrazolium chloride staining. Cardiac function and haemodynamic performance were evaluated. Infarct size was significantly reduced in PGN- or Pam3CSK4-treated mice compared with untreated I/R mice. Administration of TLR2 ligands improved cardiac function following I/R. PGN treatment increased the levels of phospho-Akt and phospho-GSK-3 beta (glycogen synthase kinase-3 beta), compared with untreated I/R hearts. PGN stimulation increased TLR2 tyrosine phosphorylation and association of the p85 subunit of PI3K with TLR2. To investigate the role of PI3K/Akt signalling in PGN-induced cardioprotection, we administered the PI3K inhibitor, Wortmannin, to the mice 15 min before PGN treatment. We also administered PGN to kinase-deficient Akt (kdAkt) transgenic mice 1 h before myocardial I/R. Both PI3K inhibition and kdAkt mice abolished the cardioprotection induced by PGN. To examine the role of TLR2 in PGN-induced cardioprotection, we administrated PGN to TLR2 knockout mice 1 h before the hearts were subjected to I/R. PGN-induced cardioprotection was lost in TLR2-deficient mice.These results demonstrate that TLR2 ligands induced cardioprotection, which is mediated through a TLR2/PI3K/Akt-dependent mechanism.