Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways
Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways
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DOI：
10.1007/s00424-007-0321-4
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发表时间：
2008-01-01
影响因子：
4.5
通讯作者：
Bian, Jin-Song
中科院分区：
文献类型：
--
作者：
Hu, Yeshi;Chen, Xin;Bian, Jin-Song
我们先前报道了硫化氢(H_2S)预适应(SP)对大鼠心肌细胞的缺血保护作用。本研究旨在通过研究细胞外信号调节激酶(ERK1/2)和磷脂酰肌醇3-激酶(PI3K)/Akt的作用来阐明SP诱导心肌保护的信号机制。我们发现，NaHS(一种硫化氢供体)预处理三个周期显著减少了心肌梗死面积，并改善了心脏的收缩功能。NaHS(1-100mM)可浓度依赖性地增加心肌细胞存活率和棒状心肌细胞百分率。PD 98059阻断ERK1/2，LY-294002或Akt抑制剂Ⅲ阻断PI3K/Akt均可显著减弱SP的心脏保护作用，提示ERK1/2和PI3K/Akt均触发并介导了SP的心脏保护作用。此外，SP还可诱导心肌细胞ERK1/2和Akt的磷酸化。ATP敏感性钾通道(K-ATP)阻断剂格列本脲和蛋白激酶C(PKC)特异性阻断剂白屈菜红碱均可减弱SP诱导的ERK1/2的磷酸化。此外，缺血预适应诱导的ERK1/2激活可通过抑制内源性硫化氢的产生而被逆转，提示缺血预适应诱导的ERK1/2激活至少部分是由内源性硫化氢介导的。总之，K-ATP/PKC/ERK1/2和PI3K/Akt通路参与了SP诱导的心肌保护作用。
We previously reported that hydrogen sulfide (H2S) preconditioning (SP) produces cardioprotective effects against ischemia in rat cardiac myocytes. The present study aims to elucidate the signaling mechanisms involved in SP-induced cardioprotection by investigating the role of extracellular signal regulated kinase (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt. We found that preconditioning with NaHS (a H2S donor) for three cycles significantly decreased myocardial infarct size and improved heart contractile function in the isolated rat hearts. NaHS (1-100 mu M) concentration-dependently increased cell viability and percentage of rod-shaped cardiac myocytes. Blockade of ERK1/2 with PD 98059 or PI3K/Akt with LY-294002 or Akt inhibitor III during either preconditioning or ischemia periods significantly attenuated the cardioprotection of SP, suggesting that both ERK1/2 and PI3K/Akt triggered and mediated the cardioprotection of SP. Moreover, SP induced ERK1/2 and Akt phosphorylation in isolated hearts. The phosphorylation of ERK1/2 induced by SP was attenuated by either glibenclamide, an ATP-sensitive K+ channel (K-ATP) blocker, or chelerythrine, a specific protein kinase C (PKC) blocker. In addition, ischemic-preconditioning-induced ERK1/2 activation was reversed by inhibiting endogenous H2S production, suggesting that ERK1/2 activation induced by ischemic preconditioning was, at least partly, mediated by endogenous H2S. In conclusion, K-ATP/PKC/ERK1/2 and PI3K/Akt pathways contributed to SP-induced cardioprotection.