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

作者全名："Yu, Huilin; Liu, Qian; Chen, Guodong; Huang, Longxiang; Luo, Minghao; Lv, Dingyi; Luo, Suxin"

作者地址："[Yu, Huilin; Liu, Qian; Chen, Guodong; Huang, Longxiang; Luo, Minghao; Lv, Dingyi; Luo, Suxin] Chongqing Med Univ, Dept Cardiol, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Yu, Huilin; Liu, Qian; Chen, Guodong; Luo, Minghao; Lv, Dingyi] Chongqing Med Univ, Inst Life Sci, Chongqing 400016, Peoples R China"

通信作者："Luo, MH; Lv, DY; Luo, SX (通讯作者)，Chongqing Med Univ, Dept Cardiol, Affiliated Hosp 1, Chongqing 400016, Peoples R China."

来源：INTERNATIONAL IMMUNOPHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000792893900002

JCR分区：Q1

影响因子：5.6

年份：2022

卷号：106

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Sepsis; AMPK; SIRT3; eNOS; Endothelial dysfunction

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-kappa B 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-kappa B 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."

基金机构：National Natural Science Foundation of China [82070238]

基金资助正文：Funding This work was supported by the National Natural Science Foundation of China (82070238) .