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Protective Role of Endothelial SIRT1 in Deep Vein Thrombosis and Hypoxia-induced Endothelial Dysfunction Mediated by NF-κB Deacetylation

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Abstract

Venous hypoxia is considered as the major pathogenetic mechanism linking blood flow stagnancy with deep vein thrombosis (DVT). Our previous study showed that activating SIRT1 may attenuate inferior vena cava (IVC) stenosis-induced DVT in rats. This study was aimed to investigate the role of endothelial SIRT1 in DVT and hypoxia-induced endothelial dysfunction as well as the underlying mechanism. Protein profiling of IVCs and blood plasma of DVT rats induced by IVC stenosis was analysed by 4D Label free proteomics analysis. To verify the independent role of SIRT1 in DVT and oxygen–glucose deprivation (OGD)-induced endothelial dysfunction, SIRT1 specific activator SRT1720 and SIRT1 knockdown in both local IVCs and endothelial cells were employed. Moreover, the role of the NF-κB were investigated using NF-κB inhibitor caffeic acid phenethyl ester (CAPE). SRT1720 significantly inhibited thrombus burden, leukocytes infiltration, protein expressions of cell adhesion molecules and chemokines, as well as acetylation level of NF-κB/p65 in wild DVT rats, while these protective effects of SRT1720 were abolished in rats with SIRT1 knockdown in local IVCs. In vitro, SRT1720 protected endothelial cells against OGD-induced dysfunction characterized with enhanced adhesion of monocytes as well as the protein expressions of cell adhesion molecules and chemokines, whereas these protective effects of SRT1720 were vanished by SIRT1 stable knockdown. Furthermore, CAPE attenuated endothelial cell dysfunction and abolished these effects of SIRT1 knockdown. Collectively, these data suggested that endothelial SIRT1 plays an independent role in ameliorating hypoxia-induced endothelial dysfunction and thrombotic inflammation in DVT, and this effect is mediated by NF-κB deacetylation.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

Ace-p65:

Acetylated-NF-κB p65

CAPE:

Caffeic acid phenethyl ester

DVT:

Deep vein thrombosis

Foxo:

Forkhead box class

ICAM-1:

Intercellular cell adhesion molecule-1

IVC:

Inferior vena cava

MCP-1:

Monocyte chemotactic protein 1

NF-κB:

Nuclear factor kappa B

NC:

Negative control

OGD:

Oxygen-glucose deprivation

p-p65:

Phosphorylated-NF-κB p65

SIRT1:

Sirtuin 1

shRNA:

Short hairpin RNA

VCAM-1:

Vascular cell adhesion molecule-1

WT:

Wild type

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Funding

This work was supported by Guangzhou Science and Technology Basic and Applied Basic Research Project (No. 202002030108).

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Authors and Affiliations

  1. Experimental Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Ping Tang, Xinrong Yang, Zhongrui Wu, Wenpei Chen, Yuxin Ye, Yong Jiang, Liuqing Lin & Baoqin Lin

  2. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Yiting Wang

  3. College of Mathematics and Statistics, Shenzhen University, Shenzhen, 518060, China

    Bingqing Lin

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Contributions

All authors contributed to the study conception and design. Ping Tang performed the experiments, analysed the data and wrote the manuscript. Yiting Wang, Xinrong Yang and Zhongrui Wu performed the experiments. Wenpei Chen analysed the results. Yuxin Ye collected the data. Yong Jiang and Liuqing Lin provided vital discussions and critical review of the manuscript. Bingqing Lin analysed and interpreted data and revised the manuscript. Baoqin Lin designed research studies and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Bingqing Lin or Baoqin Lin.

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Tang, P., Wang, Y., Yang, X. et al. Protective Role of Endothelial SIRT1 in Deep Vein Thrombosis and Hypoxia-induced Endothelial Dysfunction Mediated by NF-κB Deacetylation. Inflammation 46, 1887–1900 (2023). https://doi.org/10.1007/s10753-023-01848-9

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