Sirt3 Maintains Microvascular Endothelial Adherens Junction Integrity to Alleviate Sepsis-Induced Lung Inflammation by Modulating the Interaction of VE-Cadherin and β-Catenin.

Dan-Qian Chen,Mei-Jia Shen,Hui Wang,Shan Li,Yan Li,Guo-Qiang Zhang,Yan Guo,A-Ling Tang,Meng-Chen Xiong,Franco J L

doi:10.1155/2021/8978795

Abstract

Inflammatory injury is a hallmark of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). However, the mechanisms underlying inflammatory injury remain obscure. Here, we developed the novel strategy to suppress lung inflammation through maintaining microvascular endothelial barrier integrity. VE-cadherin is the main adherens junction protein that interacts with β-catenin and forms a complex. We found that lung inflammation was accompanied by decreased VE-cadherin expression and increased β-catenin activity in animal models and human pulmonary microvascular endothelial cells (HPMECs), illuminating the relationship among VE-cadherin/β-catenin complex, microvascular endothelial barrier integrity, and inflammation. Furthermore, we showed that the VE-cadherin/β-catenin complex dissociated upon lung inflammation, while Sirt3 promoted the stability of such a complex. Sirt3 was decreased during lung inflammation in vivo and in vitro. Sirt3 deficiency not only led to the downregulation of VE-cadherin but also enhanced the transcriptional activity of β-catenin that further increased β-catenin target gene MMP-7 expression, thereby promoting inflammatory factor COX-2 expression. Sirt3 overexpression promoted VE-cadherin expression, inhibited β-catenin transcriptional activity, strengthened the stability of the VE-cadherin/β-catenin complex, and suppressed inflammation in HPMECs. Notably, Sirt3 deficiency significantly damaged microvascular endothelial barrier integrity and intensified lung inflammation in animal model. These results demonstrated the role of Sirt3 in modulating microvascular endothelial barrier integrity to inhibit inflammation. Therefore, strategies that aim at enhancing the stability of endothelial VE-cadherin/β-catenin complex are potentially beneficial for preventing sepsis-induced lung inflammation.

Highlights

Sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is characterized by severe hypoxemia and acute respiratory failure and results in pulmonary vascular injury, edema formation, and inflammation [1, 2]
Compared with the sham-operated group, CLP surgery induced lung neutrophil infiltration and cellular debris deposition in a time-dependent manner. These results demonstrated the successful establishment of ALI models
Since the adherens junctional integrity plays an important role in maintaining lung function and preventing inflammatory injury [37], we determined the protein expression of VE-cadherin, an important microvascular endothelial adherens junction protein

Summary

Introduction

Sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is characterized by severe hypoxemia and acute respiratory failure and results in pulmonary vascular injury, edema formation, and inflammation [1, 2]. Microvascular endothelial barrier dysfunction, the main pathophysiological feature of ARDS/ALI, induces capillary leakage and edema that further intensifies inflammatory injury, causing high morbidity and mortality [2]. Inflammatory mediators that target the adherens junction destroy microvascular endothelial cell junctions and promote vascular permeability [3]. Adherens junctions are composed of transmembrane proteins and form the interaction between adjacent cells, which maintains the integrity of the microvascular endothelial monolayer and modulates its barrier. A single span transmembrane, the vascular endothelial cadherin (VE-cadherin) is the main adherens junction protein that is linked to the cortical F-actin cytoskeleton intracellularly in the vascular endothelial cell. In a vicious circle, VE-cadherin undergoes phosphorylation, destabilization, and internalization that directly damages the microvascular endothelial barrier and intensifies inflammation [4, 5]. In the meantime, sepsisinduced inflammation contributes to the breakdown of the microvascular endothelial barrier that further amplifies inflammation [6]

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Discussion

Conclusion