Metformin ameliorates endotoxemia-induced endothelial pro-inflammatory responses via AMPK-dependent mediation of HDAC5 and KLF2.
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 (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 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.
['Tian|Rui|R|', 'Li|Ranran|R|', 'Liu|Yiyun|Y|', 'Liu|Jialin|J|', 'Pan|Tingting|T|', 'Zhang|Ruyuan|R|', 'Liu|Bingya|B|', 'Chen|Erzhen|E|', 'Tang|Yaoqing|Y|', 'Qu|Hongping|H|']
D055372:AMP-Activated Protein Kinases D000620:Aminoimidazole Carboxamide D000818:Animals D001549:Benzamides D002448:Cell Adhesion D018920:Coculture Techniques D019446:Endotoxemia D005786:Gene Expression Regulation D018922:HL-60 Cells D006655:Histone Deacetylases D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D007004:Hypoglycemic Agents D051741:Kruppel-Like Transcription Factors D008070:Lipopolysaccharides D008297:Male D008687:Metformin D051379:Mice D008810:Mice, Inbred C57BL D010766:Phosphorylation D012265:Ribonucleotides D014409:Tumor Necrosis Factor-alpha D019010:Vascular Cell Adhesion Molecule-1
KLF2 Sepsis AMPK activation Inflammation HDAC5 phosphorylation Endothelial cells