Scholarlink

Background <p>Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The vascular endothelial cells (VECs) play a pivotal role in the progression of sepsis-induced vascular leakage. While therapeutic strategies targeting pathogen elimination and inflammation exist, direct interventions on the endothelial barrier are limited. The mechanisms of endothelial damage related to mitochondrial dysfunction during sepsis require further elucidation.</p> Methods <p>The study utilized a cecal ligation and puncture (CLP) rat model of sepsis and lipopolysaccharide (LPS)-stimulated VECs to investigate vascular leakage mechanisms. These models were utilized to investigate the changes in vascular permeability, mitochondrial function and protein crotonylation in VECs, aiming to identify potential therapeutic targets for sepsis.</p> Results <p>In septic rats, significant lung injury and increased vascular leakage were observed, linked to mitochondrial dysfunction and decreased survival rates. A marked downregulation of Platelet Activating Factor Acetylhydrolase 2 (PAFAH2) in VECs was identified post-sepsis, causing an upregulation of Enoyl-CoA Hydratase, Short Chain 1 (ECHS1), which inhibited crotonylation and compromised mitochondrial function, leading to increased apoptosis of VECs. Restoration experiments showed that modulating PAFAH2 and ECHS1 levels could mitigate these adverse effects. PAFAH2 overexpression alleviated sepsis-induced vascular leakage by downregulating ECHS1 and enhancing crotonylation.</p> Conclusions <p>The study identifies the PAFAH2-ECHS1 pathway as a critical axis in sepsis-induced vascular leakage, influencing mitochondrial function and crotonylation, which leads to endothelial apoptosis. These insights could guide the development of new therapies targeting the endothelial barrier for treating sepsis.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

PAFAH2 deficiency drives sepsis-induced vascular leakage by promoting ECHS1-mediated suppression of protein crotonylation and mitochondrial dysfunction

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月14日

查看全文
  • Ruibo Yang,
  • Yuxi Zhang,
  • Yinyu Wu,
  • Weichao Li,
  • Yue Zhang,
  • Daiqin Bao,
  • Xiaoli Ran,
  • Jun Zhang,
  • Yunqin Ren,
  • Han She,
  • Deyu Zuo,
  • Yaling Wang,
  • Yi Hu,
  • Qingxiang Mao

摘要

Background

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The vascular endothelial cells (VECs) play a pivotal role in the progression of sepsis-induced vascular leakage. While therapeutic strategies targeting pathogen elimination and inflammation exist, direct interventions on the endothelial barrier are limited. The mechanisms of endothelial damage related to mitochondrial dysfunction during sepsis require further elucidation.

Methods

The study utilized a cecal ligation and puncture (CLP) rat model of sepsis and lipopolysaccharide (LPS)-stimulated VECs to investigate vascular leakage mechanisms. These models were utilized to investigate the changes in vascular permeability, mitochondrial function and protein crotonylation in VECs, aiming to identify potential therapeutic targets for sepsis.

Results

In septic rats, significant lung injury and increased vascular leakage were observed, linked to mitochondrial dysfunction and decreased survival rates. A marked downregulation of Platelet Activating Factor Acetylhydrolase 2 (PAFAH2) in VECs was identified post-sepsis, causing an upregulation of Enoyl-CoA Hydratase, Short Chain 1 (ECHS1), which inhibited crotonylation and compromised mitochondrial function, leading to increased apoptosis of VECs. Restoration experiments showed that modulating PAFAH2 and ECHS1 levels could mitigate these adverse effects. PAFAH2 overexpression alleviated sepsis-induced vascular leakage by downregulating ECHS1 and enhancing crotonylation.

Conclusions

The study identifies the PAFAH2-ECHS1 pathway as a critical axis in sepsis-induced vascular leakage, influencing mitochondrial function and crotonylation, which leads to endothelial apoptosis. These insights could guide the development of new therapies targeting the endothelial barrier for treating sepsis.