Li Jia, Zhang Haifeng, Wu Feng, Nan Ying, Ma Heng, Guo Wenyi, Wang Haichang, Ren Jun, Das Undurti N, Gao Feng
Department of Physiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Crit Care Med. 2008 May;36(5):1551-8. doi: 10.1097/CCM.0b013e3181782335.
Intensive insulin therapy with tight glucose control is known to result in reduced morbidity and mortality in inflammation-related critical illness. Tumor necrosis factor (TNF)-alpha induction in myocardial infarction may trigger inflammation and have detrimental effects on cardiomyocytes. This study was designed to investigate whether insulin attenuates TNF-alpha induction in acute myocardial ischemia/reperfusion (MI/R) and the underlying signaling mechanisms.
Randomized experimental study.
Research laboratory.
Sprague-Dawley rats.
Anesthetized rats were subjected to MI/R (30 mins/3 hrs) and were treated with saline, glucose-insulin-potassium, or glucose-potassium infusion (4 mL/kg/hr intravenously). In vitro study was performed on cultured cardiomyocytes subjected to simulated ischemia/reperfusion (SI/R).
In vivo treatment with glucose-insulin-potassium, but not glucose-potassium, significantly attenuated inflammatory response as evidenced by decreased TNF-alpha induction and myocardial myeloperoxidase activity, with concurrent reduction in creatine kinase activity and myocardial infarction compared with those in control rats. In cultured cardiomyocytes subjected to SI/R, insulin reduced TNF-alpha induction and increased Akt and endothelial nitric oxide synthase (eNOS) phosphorylation and subsequent nitric oxide (NO) production. Inhibition of insulin-stimulated NO production using either the PI3K inhibitor wortmannin or the NOS inhibitor L-NAME blocked TNF-alpha reduction afforded by insulin. Furthermore, the suppression on TNF-alpha by either insulin or TNF-alpha neutralizing antibody improved viability and reduced apoptosis of cardiomyocytes subjected to SI/R.
Our data showed that insulin inhibits ischemia/reperfusion-induced TNF-alpha production through the Akt-activated and eNOS-NO-dependent pathway in cardiomyocytes. The anti-inflammatory property elicited by insulin may contribute to its cardioprotective and prosurvival effects in the critically ill.
强化胰岛素治疗并严格控制血糖已知可降低炎症相关危重症的发病率和死亡率。心肌梗死中肿瘤坏死因子（TNF）-α的诱导可能引发炎症并对心肌细胞产生有害影响。本研究旨在探讨胰岛素是否能减轻急性心肌缺血/再灌注（MI/R）中TNF-α的诱导及潜在的信号传导机制。
随机实验研究。
研究实验室。
Sprague-Dawley大鼠。
将麻醉的大鼠进行MI/R（30分钟/3小时），并分别给予生理盐水、葡萄糖-胰岛素-钾或葡萄糖-钾输注（静脉内4毫升/千克/小时）。对培养的心肌细胞进行模拟缺血/再灌注（SI/R）的体外研究。
与对照大鼠相比，葡萄糖-胰岛素-钾而非葡萄糖-钾的体内治疗显著减轻了炎症反应，表现为TNF-α诱导减少和心肌髓过氧化物酶活性降低，同时肌酸激酶活性和心肌梗死面积也减少。在经历SI/R的培养心肌细胞中，胰岛素降低了TNF-α的诱导，并增加了Akt和内皮型一氧化氮合酶（eNOS）的磷酸化以及随后的一氧化氮（NO）生成。使用PI3K抑制剂渥曼青霉素或NOS抑制剂L-NAME抑制胰岛素刺激的NO生成可阻断胰岛素对TNF-α的降低作用。此外，胰岛素或TNF-α中和抗体对TNF-α的抑制作用改善了经历SI/R的心肌细胞的活力并减少了其凋亡。
我们的数据表明，胰岛素通过心肌细胞中Akt激活和eNOS-NO依赖的途径抑制缺血/再灌注诱导的TNF-α产生。胰岛素引发的抗炎特性可能有助于其在危重症中的心脏保护和促生存作用。
