SIRT3-AMPK signaling pathway as a protective target in endothelial dysfunction of early sepsis

安普克 败血症 内皮功能障碍 SIRT3 伊诺斯 内分泌学 医学 脐静脉 蛋白激酶A 内科学 AMP活化蛋白激酶 一氧化氮 磷酸化 药理学 一氧化氮合酶 生物 细胞生物学 体外 生物化学 乙酰化 基因 锡尔图因
作者
Huilin Yu,Qian Liu,Guodong Chen,Longxiang Huang,Minghao Luo,Dingyi Lv,Suxin Luo
出处
期刊:International Immunopharmacology [Elsevier]
卷期号:106: 108600-108600 被引量:20
标识
DOI:10.1016/j.intimp.2022.108600
摘要

Extensive vascular endothelial dysfunction usually occurs in sepsis, resulting in high mortality. The purpose of this study was therefore to investigate the role of AMP-dependent protein kinase (AMPK) in the aortic endothelial dysfunction of early sepsis in mice, and the relationship between AMPK and Sirtuin3 (SIRT3). Cecal ligation and puncture (CLP) surgery was performed to establish a mouse sepsis model, and human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) to mimic a sepsis model in vitro. We suppressed and increased the activities of AMPK with Dorsomorphin (CC) and Acadesine (AICAR), respectively. 3-TYP (SIRT3 inhibitor) and Honokiol (SIRT3 agonist) were used to alter SIRT3 activity. Then, the inflammatory and endothelial function parameters of the vascular tissue and survival rate were determined. In vivo, the expression of Ser1177 phosphorylation of endothelial nitric oxide synthase (p-eNOS), endothelium-dependent relaxation function, and survival decreased (P < 0.05), while NF-κB and NLRP3 pathways were activated in CLP-induced early sepsis (P < 0.05). Moreover, activation of AMPK significantly reversed the reduction of p-eNOS expression (P < 0.05), prevented endothelial dysfunction (P < 0.05), deactivated NF-κB and NLRP3 pathways (P < 0.05), and improved survival (P < 0.05) in septic mice. However, AMPK inhibition led to opposite effects (P < 0.05). In addition, changing the activity of AMPK had little effect on SIRT3 expression (P > 0.05), while the expression of p-AMPK varied with the inhibition or activation of SIRT3 (P < 0.05), which was further demonstrated using in vitro experiments. Together, the results showed that the SIRT3-AMPK signaling pathway played an important role in inhibiting vascular inflammation and endothelial dysfunction during early sepsis.
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