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  • br Author contributions br Transparency document br Introduc


    Author contributions
    Transparency document
    Introduction Sepsis, characterized by dysregulation of systemic immunity and subsequent multiple organ failure, is the leading cause of death among hospitalized patients [1,2]. Despite substantial efforts in understanding the pathophysiology of sepsis as well as investigation of therapeutic strategies, the effective treatment of sepsis remains a clinical challenge. Endothelial EPZ031686 lining along the inner surface of the vasculature play a significant role in maintaining vascular homeostasis [3]. In the early stage of sepsis, exaggerated endothelial activation, vascular leakage, disturbance of blood flow, as well as other derangements cause the loss of vascular integrity, which contributes significantly to sepsis-associated organ failure. Therapies interfering endothelial activation are potential to attenuate sepsis-induced organ dysfunction. Lipopolysaccharide (LPS), also known as endotoxin, is the key structural component of the wall of gram-negative bacteria and is a critical factor that triggers the pathogenesis of sepsis [4]. Circulating LPS activates endothelial cells, leading to the production of inflammatory cytokines, expression of adhesion molecules, leukocyte recruitment, and loss of vascular integrity. In addition, LPS activates monocytes and macrophages in the circulation to release pro-inflammatory cytokines, such as tumor necrosis factor-⍺ (TNF⍺), which in turn modulate endothelial pro-inflammatory activation [5,6]. The active molecular responses in inflammation requires intensive metabolic support and modulation EPZ031686 of the metabolic pathways might be a novel strategy to restrict inflammatory injury [7]. Metformin, characterized as a metabolic regulator, is widely used as a first-line anti-diabetic drug for type-II diabetes [8]. Metformin activates adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) which plays a pivotal role in maintaining the metabolic homeostasis [9]. Recently, several studies revealed the anti-inflammatory effects of metformin in sepsis [10,11]. However, the underlying mechanisms remains not fully understood. The regulation of gene expression by histone deacetylases (HDACs) is a kind of post translational modification. HDAC activity is demonstrated to be highly enhanced in sepsis, hemorrhagic shock, and other acute injuries [[12], [13], [14]], leading to the organ dysfunction. The beneficial effects of HDAC inhibition suggests that controlling HDAC activity is a potential therapeutic strategy in these diseases [15,16]. Kruppel-like factor 2 (KLF2) as a vascular-protective transcription factor plays an important role in maintaining endothelial function and vascular integrity [[17], [18], [19]]. KLF2 in endothelial cells is well known to be highly sensitive to fluid shear stress. Recent studies have demonstrated that the regulation of KLF2 by fluid shear stress is controlled by HDAC5, one of the Class IIa HDACs of which the activity is regulated by their phosphorylation-dependent nuclear/cytoplasm shuttling [20]. AMPK has been reported to induce HDAC5 cytoplasm/nuclear translocation in cellular adaptation to hypoxia [21].
    Materials and methods
    Discussion In the early stage of sepsis, endothelial cells are crucial in the onset of pro-inflammatory responses and the inhibition of endothelial inflammation is expected to attenuate sepsis-associated multiple organ failure. In the present study, we explored the regulatory mechanism of AMPK activators in endotoxemia-induced endothelial inflammation. We demonstrated that by activating AMPK, metformin and AICAR increased HDAC5 phosphorylation and led to the upregulation of KLF2, resulting in the inhibition of endotoxemia-induced VCAM1 expression both in vitro and in vivo (as summarized in Fig. 8). Our results indicated that AMPK-mediated HDAC5 phosphorylation and KLF2 restoration is, at least partially, responsible to the anti-inflammatory effects of metformin in endotoxemia-induced endothelial activation, which has important implications for interfering therapies of sepsis.