Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism
Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism
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褪黑激素通过 PI3K/Akt 依赖性机制减轻脓毒症引起的心脏功能障碍
DOI：
10.1007/s00395-015-0526-1
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发表时间：
2016-01-01
影响因子：
9.5
通讯作者：
Sun, Lijun
中科院分区：
文献类型：
--
作者：
An, Rui;Zhao, Lei;Sun, Lijun
心肌功能不全是脓毒症的重要表现。以前的研究表明，褪黑激素对败血症有保护作用。此外，已报道磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（Akt）信号通路的激活在脓毒症中是有益的。然而，PI 3 K/Akt信号转导在褪黑素对脓毒症诱导的心肌功能障碍的保护作用中的作用仍不清楚。本研究采用PI 3 K抑制剂LY 294002研究PI 3 K/Akt信号通路在褪黑素抗脓毒症心肌损伤中的作用。采用盲肠结扎穿孔术（CLP）建立大鼠脓毒症模型。褪黑激素腹腔注射（30 mg/kg）。评估存活率、心肌损伤和心脏功能指标、血清乳酸脱氢酶水平、炎性细胞因子水平、氧化应激水平和心肌细胞凋亡程度。结果表明，褪黑激素管理CLP手术后提高生存率和心功能，减轻心肌损伤和细胞凋亡，降低血清乳酸脱氢酶水平。褪黑激素可降低炎症细胞因子TNF-α、IL-1β和HMGB 1的产生，增加抗氧化酶活性，并降低氧化损伤标志物的表达。蛋白质印迹法测定磷酸化Akt（p-Akt）、非磷酸化Akt（Akt）、Bcl-2和Bax的水平。褪黑激素增加p-Akt水平，这表明Akt通路激活。褪黑激素诱导Bcl-2表达升高，Bax表达降低，提示抑制细胞凋亡。褪黑素的所有保护作用均被PI 3 K抑制剂LY 294002所消除。总之，我们的研究结果表明，褪黑激素减轻心肌损伤脓毒症通过PI 3 K/Akt信号激活。
Myocardial dysfunction is an important manifestation of sepsis. Previous studies suggest that melatonin is protective against sepsis. In addition, activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway has been reported to be beneficial in sepsis. However, the role of PI3K/Akt signaling in the protective effect of melatonin against sepsis-induced myocardial dysfunction remains unclear. Here, LY294002, a PI3K inhibitor, was used to investigate the role of PI3K/Akt signaling in mediating the effects of melatonin on sepsis-induced myocardial injury. Cecal ligation and puncture (CLP) surgery was used to establish a rat model of sepsis. Melatonin was administrated to rats intraperitoneally (30 mg/kg). The survival rate, measures of myocardial injury and cardiac performance, serum lactate dehydrogenase level, inflammatory cytokine levels, oxidative stress level, and the extent of myocardial apoptosis were assessed. The results suggest that melatonin administration after CLP surgery improved survival rates and cardiac function, attenuated myocardial injury and apoptosis, and decreased the serum lactate dehydrogenase level. Melatonin decreased the production of the inflammatory cytokines TNF-α, IL-1β, and HMGB1, increased anti-oxidant enzyme activity, and decreased the expression of markers of oxidative damage. Levels of phosphorylated Akt (p-Akt), unphosphorylated Akt (Akt), Bcl-2, and Bax were measured by Western blot. Melatonin increased p-Akt levels, which suggests Akt pathway activation. Melatonin induced higher Bcl-2 expression and lower Bax expression, suggesting inhibition of apoptosis. All protective effects of melatonin were abolished by LY294002, the PI3K inhibitor. In conclusion, our results demonstrate that melatonin mitigates myocardial injury in sepsis via PI3K/Akt signaling activation.