HSF1 Alleviates Microthrombosis and Multiple Organ Dysfunction in Mice with Sepsis by Upregulating the Transcription of Tissue-Type Plasminogen Activator.

Abstract

Sepsis is a life-threatening complication of infection closely associated with coagulation abnormalities. Heat shock factor 1 (HSF1) is an important transcription factor involved in many biological processes, but its regulatory role in blood coagulation remained unclear. We generated a sepsis model in HSF1-knockout mice to evaluate the role of HSF1 in microthrombosis and multiple organ dysfunction. Compared with septic wild-type mice, septic HSF1-knockout mice exhibited a greater degree of lung, liver, and kidney tissue damage, increased fibrin/: fibrinogen deposition in the lungs and kidneys, and increased coagulation activity. RNA-seq analysis revealed that tissue-type plasminogen activator (t-PA) was upregulated in the lung tissues of septic mice, and the level of t-PA was significantly lower in HSF1-knockout mice than in wild-type mice in sepsis. The effects of HSF1 on t-PA expression were further validated in HSF1-knockout mice with sepsis and in vitro in mouse brain microvascular endothelial cells using HSF1 RNA interference or overexpression under lipopolysaccharide stimulation. Bioinformatics analysis, combined with electromobility shift and luciferase reporter assays, indicated that HSF1 directly upregulated t-PA at the transcriptional level. Our results reveal, for the first time, that HSF1 suppresses coagulation activity and microthrombosis by directly upregulating t-PA, thereby exerting protective effects against multiple organ dysfunction in sepsis.

• Authors: Tao Li, Huan Chen, Xueyan Shi, Leijing Yin, Chuyi Tan, Jia Gu, Yanjuan Liu, Caiyan Li, Gui Xiao, Ke Liu, Meidong Liu, Sipin Tan, Zihui Xiao, Huali Zhang, Xianzhong Xiao
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 121 Issue 8 Pg. 1066-1078 (Aug 2021) ISSN: 2567-689X [Electronic] Germany
• PMID: 33296942 (Publication Type: Journal Article)
• Copyright: Thieme. All rights reserved.

Chemical References

• Heat Shock Transcription Factors
• Hsf1 protein, mouse
• Tissue Plasminogen Activator

Topics

• Animals
• Blood Coagulation
• Cell Line
• Disease Models, Animal
• Female
• Heat Shock Transcription Factors (genetics, metabolism)
• Male
• Mice, Knockout
• Multiple Organ Failure (blood, genetics, microbiology, prevention & control)
• Sepsis (blood, genetics, microbiology)
• Thrombosis (blood, genetics, microbiology, prevention & control)
• Tissue Plasminogen Activator (blood, genetics)
• Transcriptional Activation
• Up-Regulation