Metformin ameliorates endotoxemia-induced endothelial pro-inflammatory responses via AMPK-dependent mediation of HDAC5 and KLF2

Publication date: Available online 16 April 2019Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Rui Tian, Ranran Li, Yiyun Liu, Jialin Liu, Tingting Pan, Ruyuan Zhang, Bingya Liu, Erzhen Chen, Yaoqing Tang, Hongping QuAbstractExaggerated 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 (HDAC5) 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 ⍺ (TNF⍺)-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 ...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research