Fan Ting-Ting, Feng Xuan-Yun, Yang Yuan-Zheng, Gao Feng, Liu Qiong
Department of Emergency, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Department of Emergency, Chengdu First People's Hospital, Sichuan 610016, PR China.
Department of Emergency, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
Cytokine. 2017 Aug;96:208-216. doi: 10.1016/j.cyto.2017.04.018. Epub 2017 Apr 28.
A key component during sepsis is the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, of which the PI3K-γ isoform is a major regulator in many inflammatory responses. However, the role of PI3K-γ in the development of sepsis-induced myocardial dysfunction (SIMD) is unknown. In this study, we established a model of SIMD induced by lipopolysaccharide (LPS), subsequently used the selective inhibitor LY294002 and AS605240 to block the effect of PI3K and PI3K-γ, respectively. Cardiac function was evaluated by echocardiography, hearts were obtained for histological and protein expression examinations. ELISA was used to measure the serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), cardiac troponin I (cTnI) and heart-type fatty acid binding protein (H-FABP). LPS-treated mice showed an increase to cardiac inflammation, myocardial damage and production of TNF-α, IL-6, NF-κB, cTnI and H-FABP. Administration of AS605240 to LPS-treated mice reduced some patho-physiological characteristics of SIMD and reduced TNF-α, IL-6, cTnI and H-FABP production. However, administration of LY294002 did not improve those same conditions. The results showed that PI3K-γ is likely a crucial element in SIMD by regulating the PI3K/Akt pathway, and become a new marker of myocardial injury. Inhibition of PI3K-γ might be a potential therapeutic target in SIMD.
脓毒症期间的一个关键组成部分是磷酸肌醇3激酶（PI3K）/蛋白激酶B（Akt）信号通路，其中PI3K-γ亚型是许多炎症反应的主要调节因子。然而，PI3K-γ在脓毒症诱导的心肌功能障碍（SIMD）发展中的作用尚不清楚。在本研究中，我们建立了脂多糖（LPS）诱导的SIMD模型，随后分别使用选择性抑制剂LY294002和AS605240阻断PI3K和PI3K-γ的作用。通过超声心动图评估心脏功能，获取心脏进行组织学和蛋白表达检查。采用酶联免疫吸附测定法（ELISA）测量血清中肿瘤坏死因子α（TNF-α）、白细胞介素-6（IL-6）、心肌肌钙蛋白I（cTnI）和心型脂肪酸结合蛋白（H-FABP）的水平。LPS处理的小鼠心脏炎症、心肌损伤以及TNF-α、IL-6、NF-κB、cTnI和H-FABP的产生均增加。给LPS处理的小鼠施用AS605240可减轻SIMD的一些病理生理特征，并减少TNF-α、IL-6、cTnI和H-FABP的产生。然而，施用LY294002并未改善这些情况。结果表明，PI3K-γ可能通过调节PI3K/Akt通路成为SIMD的关键因素，并成为心肌损伤的新标志物。抑制PI3K-γ可能是SIMD的一个潜在治疗靶点。
