GSK-3β inhibition protects the rat heart from the lipopolysaccharide-induced inflammation injury via suppressing FOXO3A activity
GSK-3β inhibition protects the rat heart from the lipopolysaccharide-induced inflammation injury via suppressing FOXO3A activity
复制标题
GSK–3β 抑制通过抑制 FOXO3A 活性保护大鼠心脏免受脂多糖–诱导的炎症损伤
DOI：
10.1111/jcmm.14656
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发表时间：
2019-09-10
影响因子：
5.3
通讯作者：
Peng, Luying
中科院分区：
文献类型：
--
作者：
Li, Zhigang;Zhu, Huifang;Peng, Luying
脓毒症引起的心功能不全是重症监护病房死亡的主要原因。先前的研究表明GSK-3 β参与脓毒症的调节。然而，GSK-3 β调节内毒素脂多糖（LPS）诱导的脓毒性心肌功能障碍的信号转导细节仍不清楚。在此，基于大鼠脓毒性心肌损伤模型，我们发现LPS可诱导原代心肌细胞GSK-3 β活性位点（Y216）磷酸化，并上调FOXO 3A水平。GSK-3 β抑制剂显著降低FOXO 3A表达，并通过β-连环蛋白敲低进一步逆转。GSK-3 β的这种药理学抑制通过介导β-连环蛋白信号传导减弱LPS诱导的细胞损伤，这可以通过FOXO 3A激活来消除。在体内，GSK-3 β抑制持续改善心脏功能并减轻LPS诱导的心脏损伤。此外，GSK-3 β抑制剂可阻断LPS诱导的心肌细胞炎症因子的增加，抑制ERK和NF-κ B通路，并通过激活AMP活化蛋白激酶（AMPK）抑制心肌细胞凋亡。我们的研究结果表明，GSK-3 β抑制剂可减轻内毒素诱导的心肌损伤，内毒素介导FOXO 3A的激活，这提示了脓毒性心功能障碍治疗的潜在靶点。
Sepsis-induced cardiac dysfunction represents a main cause of death in intensive care units. Previous studies have indicated that GSK-3 beta is involved in the modulation of sepsis. However, the signalling details of GSK-3 beta regulation in endotoxin lipopolysaccharide (LPS)-induced septic myocardial dysfunction are still unclear. Here, based on the rat septic myocardial injury model, we found that LPS could induce GSK-3 beta phosphorylation at its active site (Y216) and up-regulate FOXO3A level in primary cardiomyocytes. The FOXO3A expression was significantly reduced by GSK-3 beta inhibitors and further reversed through beta-catenin knock-down. This pharmacological inhibition of GSK-3 beta attenuated the LPS-induced cell injury via mediating beta-catenin signalling, which could be abolished by FOXO3A activation. In vivo, GSK-3 beta suppression consistently improved cardiac function and relieved heart injury induced by LPS. In addition, the increase in inflammatory cytokines in LPS-induced model was also blocked by inhibition of GSK-3 beta, which curbed both ERK and NF-kappa B pathways, and suppressed cardiomyocyte apoptosis via activating the AMP-activated protein kinase (AMPK). Our results demonstrate that GSK-3 beta inhibition attenuates myocardial injury induced by endotoxin that mediates the activation of FOXO3A, which suggests a potential target for the therapy of septic cardiac dysfunction.