2. Academic Validation
  3. GAS6 attenuates sepsis-induced cardiac dysfunction through NLRP3 inflammasome-dependent mechanism

GAS6 attenuates sepsis-induced cardiac dysfunction through NLRP3 inflammasome-dependent mechanism

  • Free Radic Biol Med. 2024 Jan:210:195-211. doi: 10.1016/j.freeradbiomed.2023.11.007.
Ting Ji 1,  Qiong Liu 1,  Liming Yu 2,  Wangrui Lei 1,  Chenxi Lu 1,  Junmin Chen 1,  Xin Xie 1,  Zhenhua Zhang 3,  Zhenxing Liang 4,  Chao Deng 5,  Ying Chen 6,  Jun Ren 7,  Yang Yang 8
Affiliations

Affiliations

  • 1 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China; Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, 710021, Xi'an, China.
  • 2 Department of Cardiovascular Surgery, General Hospital of Northern Military Area Command, Shenyang, 110016, China.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 4 Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 5 Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 6 Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 7 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China. Electronic address: jren_aldh2@outlook.com.
  • 8 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China; Department of Neurology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, 710021, Xi'an, China. Electronic address: yang200214yy@nwu.edu.cn.
PMID: 37979891 DOI: 10.1016/j.freeradbiomed.2023.11.007
Abstract

Sepsis is a major health threat and often results in heart failure. Growth arrest-specific gene 6 (GAS6), a 75-kDa vitamin K-dependent protein, participates in immune regulation and inflammation through binding to AXL (the TAM Receptor family). This study was designed to examine the myocardial regulatory role of GAS6 in sepsis. Serum GAS6 levels were increased in septic patients and mice while myocardial GAS6 levels were decreased in septic mice. Single-cell RNA Sequencing further revealed a decline in GAS6 levels of nearly all cell clusters including cardiomyocytes. GAS6 overexpression via adeno-associated virus 9 (AAV9) overtly improved cardiac dysfunction in cecum ligation and puncture (CLP)-challenged mice, along with alleviated mitochondrial injury, endoplasmic reticulum stress, oxidative stress, and Apoptosis. However, GAS6-elicited beneficial effects were removed by GAS6 knockout. The in vitro study was similar to these findings. Our data also noted a downstream effector role for NLRP3 in GAS6-initiated myocardial response. GAS6 knockout led to elevated levels of NLRP3, the effect of which was reconciled by GAS6 overexpression. Taken together, these results revealed the therapeutical potential of targeting GAS6/AXL-NLRP3 signaling in the management of heart anomalies in sepsis.

Keywords

CLP; GAS6; NLRP3; Sepsis; Septic myocardial injury.

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