Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion -: The roles of PI3-kinase, akt, and endothelial nitric oxide synthase phosphorylation
Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion -: The roles of PI3-kinase, akt, and endothelial nitric oxide synthase phosphorylation
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DOI：
10.1161/01.cir.0000012529.00367.0f
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发表时间：
2002-03-26
期刊：
影响因子：
37.8
通讯作者：
Ma, XL
中科院分区：
文献类型：
--
作者：
Gao, F;Gao, E;Ma, XL
背景——来自培养内皮细胞研究的最新证据表明，内皮一氧化氮合酶 (eNOS) 通过 PI3-激酶-Akt 途径磷酸化会增加 NO 的产生。本研究旨在阐明胰岛素体内抗凋亡作用所涉及的信号通路，并检验胰岛素磷酸化eNOS可能参与胰岛素在心肌缺血再灌注后的心脏保护作用的假设。 方法与结果-雄性Sprague-Dawley大鼠接受30分钟的心肌缺血和4小时的再灌注。大鼠被随机分配接受赋形剂、胰岛素、胰岛素加渥曼青霉素或胰岛素加 L-NAME。胰岛素治疗导致缺血/再灌注心肌组织中 Akt 和 eNOS 磷酸化增加 2.6 倍和 4.3 倍，并且 NO 产生显着增加。 Akt 和 eNOS 的磷酸化以及胰岛素导致 NO 产生的增加被 PI3 激酶抑制剂渥曼青霉素完全阻断。 L-NAME（一种非选择性 NOS 抑制剂）预处理对 Akt 和 eNOS 磷酸化没有影响，但显着减少 NO 产生。此外，胰岛素治疗显着减少了心肌细胞凋亡死亡（P
Background-Recent evidence from cultured endothelial cell studies suggests that phosphorylation of endothelial nitric oxide synthase (eNOS) through the PI3-kinase-Akt pathway increases NO production. This study was designed to elucidate the signaling pathway involved in the antiapoptotic effect of insulin in vivo and to test the hypothesis that phosphorylation of eNOS by insulin may participate in the cardioprotective effect of insulin after myocardial ischemia and reperfusion.Methods and Results-Male Sprague-Dawley rats were subjected to 30 minutes of myocardial ischemia and 4 hours of reperfusion. Rats were randomized to receive vehicle, insulin, insulin plus wortmannin, or insulin plus L-NAME. Treatment with insulin resulted in 2.6-fold and 4.3-fold increases in Akt and eNOS phosphorylation and a significant increase in NO production in ischemic/reperfused myocardial tissue. Phosphorylation of Akt and eNOS and increase of NO production by insulin were completely blocked by wortmannin, a PI3-kinase inhibitor. Pretreatment with L-NAME, a nonselective NOS inhibitor, had no effect on Akt and eNOS phosphorylation but significantly reduced NO production. Moreover, treatment with insulin markedly reduced myocardial apoptotic death (P