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Polydatin protects against lipopolysaccharide-induced endothelial barrier disruption via SIRT3 activation.
Wu, Jie; Deng, Zhiya; Sun, Maomao; Zhang, Weijin; Yang, Yang; Zeng, Zhenhua; Wu, Jianhua; Zhang, Qin; Liu, Yanan; Chen, Zhenfeng; Guo, Xiaohua; Zhao, Ke-Seng; Huang, Qiaobing; Chen, Zhongqing.
Afiliação
  • Wu J; Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • Deng Z; Guangdong Provincial Key Lab of Shock and Microcirculation, Department of Pathophysiology, Southern Medical University, Guangzhou, 510515, China.
  • Sun M; Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • Zhang W; Guangdong Provincial Key Lab of Shock and Microcirculation, Department of Pathophysiology, Southern Medical University, Guangzhou, 510515, China.
  • Yang Y; Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • Zeng Z; Guangdong Provincial Key Lab of Shock and Microcirculation, Department of Pathophysiology, Southern Medical University, Guangzhou, 510515, China.
  • Wu J; Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • Zhang Q; Guangdong Provincial Key Lab of Shock and Microcirculation, Department of Pathophysiology, Southern Medical University, Guangzhou, 510515, China.
  • Liu Y; Department of Geriatrics, Shantou Central Hospital, Shantou, 515000, China.
  • Chen Z; Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • Guo X; Department of Critical Care Medicine, the First People's Hospital of Chenzhou, Chenzhou, 423000, China.
  • Zhao KS; Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • Huang Q; Guangdong Provincial Key Lab of Shock and Microcirculation, Department of Pathophysiology, Southern Medical University, Guangzhou, 510515, China.
  • Chen Z; The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
Lab Invest ; 100(4): 643-656, 2020 04.
Article em En | MEDLINE | ID: mdl-31641228
ABSTRACT
In a previous study, we demonstrated the role of polydatin (PD) in protecting against multiple organ dysfunction in sepsis. The aim of this study is to investigate whether PD protects against lipopolysaccharide (LPS)-induced endothelial barrier disruption through SIRT3 activation and to disclose the underlying mechanisms. Wild-type mice were injected with LPS and Evans Blue assay was performed to evaluate vascular permeability. Primary human umbilical vein endothelial cells (HUVECs) were stimulated with LPS. Endothelial permeability was evaluated by transendothelial electrical resistance (TER) and FITC-dextran leakage. SIRT3 activity was determined by a Deacetylase Fluorometric kit, and protein expression level of SIRT3 was detected by western blotting. Mitochondrial function was evaluated by determination of ROS level, mitochondrial membrane potential and mPTP opening. In endotoxemic mice, PD pretreatment attenuated vascular leakage in multiple organs while SIRT3 inhibition with 3-TYP reversed the effects of PD. PD treatment in late sepsis also exhibited barrier protective effects. In HUVECs, PD alleviated LPS-induced F-actin rearrangement, cadherin-catenin complex dissociation and endothelial hyperpermeability, whereas 3-TYP or SIRT3 siRNA attenuated the protective effects of PD. PD enhanced SIRT3 deacetylase activity, and attenuated LPS-induced decrease in SIRT3 expression as well. Furthermore, gain-of-function and loss-of-function strategies also confirmed the role of SIRT3 in enhancing endothelial barrier integrity. It was further ascertained that PD enhanced SIRT3-mediated deacetylation of SOD2 and cyclophilin D (CypD), thus suppressing mitochondrial dysfunction and subsequent endothelial barrier dysfunction. In addition, it was revealed that RAGE was involved in LPS-regulated SIRT3 signaling. Our results suggest that polydatin protects against LPS-induced endothelial barrier disruption dependent on SIRT3 and can be applied as a potential therapy for sepsis.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estilbenos / Endotélio Vascular / Transdução de Sinais / Lipopolissacarídeos / Sirtuína 3 / Glucosídeos Limite: Animals / Humans Idioma: En Revista: Lab Invest Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estilbenos / Endotélio Vascular / Transdução de Sinais / Lipopolissacarídeos / Sirtuína 3 / Glucosídeos Limite: Animals / Humans Idioma: En Revista: Lab Invest Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China