Metformin ameliorates endotoxemia-induced endothelial pro-inflammatory responses via AMPK-dependent mediation of HDAC5 and KLF2
Metformin ameliorates endotoxemia-induced endothelial pro-inflammatory responses via AMPK-dependent mediation of HDAC5 and KLF2
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二甲双胍通过 HDAC5 和 KLF2 的 AMPK 依赖性介导改善内毒素血症诱导的内皮促炎症反应
DOI：
10.1016/j.bbadis.2019.04.009
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发表时间：
2019-06-01
影响因子：
6.2
通讯作者：
Qu, Hongping
中科院分区：
文献类型：
--
作者：
Tian, Rui;Li, Ranran;Qu, Hongping
过度的内皮促炎反应是脓毒症早期的一个标志，并有助于随后的组织损伤和器官衰竭。AMPK激活剂二甲双胍在脓毒症中的抗炎作用已被揭示。然而，其潜在机制仍未完全了解。在本研究中，我们研究了组蛋白去乙酰化酶5 （HDACS）和kruppel样因子2 （KLF2）在二甲双胍对内皮促炎反应中的潜在作用。结果显示，二甲双胍预处理增加HDAC5丝氨酸498位点磷酸化，导致KLF2上调，消除脂多糖（LPS）和肿瘤坏死因子α (TNF α)诱导的血管细胞粘附分子1 （VCAM1）上调。此外，二甲双胍能有效抑制HL60白细胞与内皮单层的粘附。此外，体内数据证实，AMPK激活通过介导HDAC5磷酸化和恢复KLF2表达，减轻了LPS诱导的内毒小鼠的局部和全身炎症。我们的研究结果表明，AMPK激活介导的HDAC5磷酸化和KLF2恢复至少部分地负责二甲双胍在内毒素血症诱导的内皮细胞中的抗炎作用，这对未来脓毒症干扰治疗的发展具有重要意义。
Exaggerated endothelial pro-inflammatory response is a hallmark in the early stage of sepsis and contributes to the subsequent tissue injury and organ failure. The anti-inflammatory effects of AMP-activated protein kinase (AMPK) activator metformin in sepsis has been revealed. However, the underlying mechanisms remain not fully understood. In the present study, the potential roles of histone deacetylase 5 (HDACS) and kruppel-like factor 2 (KLF2) in the effects of metformin on endothelial pro-inflammatory responses were investigated. The results showed that metformin pretreatment increased the phosphorylation of HDAC5 at serine 498, leading to the upregulation of KLF2, and eliminated lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF alpha)-induced upregulation of vascular cell adhesion molecule 1 (VCAM1). Furthermore, the adhesion of HL60 leukocytes to endothelial monolayer was effectively inhibited by metformin. In addition, the in vivo data confirmed that AMPK activation attenuated local and systemic inflammation in endotoxic mice induced by LPS via mediating phosphorylating HDAC5 and restoring KLF2 expression. Our findings revealed that AMPK activation-mediated HDAC5 phosphorylation and KLF2 restoration is, at least partially, responsible to the anti-inflammatory effects of metformin in endotoxemia-induced endothelial cells, which has important implications for the future development of interfering therapies of sepsis.