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

Authors:
Rui Tian
Rui Tian
Huazhong University of Science and Technology
China
Ranran Li
Ranran Li
School of Science
China
Yiyun Liu
Yiyun Liu
The First Affiliated Hospital of Chongqing Medical University
Jialin Liu
Jialin Liu
Ruijin Hospital
China
Tingting Pan
Tingting Pan
Fudan University
China
Ruyuan Zhang
Ruyuan Zhang
Ruijin Hospital
China
Bingya Liu
Bingya Liu
Ruijin Hospital
China
Erzhen Chen
Erzhen Chen
Shanghai Rui Jin Hospital

Biochim Biophys Acta Mol Basis Dis 2019 Jun 16;1865(6):1701-1712. Epub 2019 Apr 16.

Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China. Electronic address:

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.

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Source
https://linkinghub.elsevier.com/retrieve/pii/S09254439193012
Publisher Site
http://dx.doi.org/10.1016/j.bbadis.2019.04.009DOI Listing
June 2019
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