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Thromb Haemost 2021; 121(08): 1066-1078
DOI: 10.1055/a-1333-7305
Coagulation and Fibrinolysis

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

Tao Li‡   *
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
2   Department of Pathophysiology, Medical College of Jiaying University, Meizhou, Guangdong, China
,
Huan Chen‡   *
3   Postdoctoral Research Station of Clinical Medicine and Department of Hematology, the Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China
,
Xueyan Shi
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Leijing Yin
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Chuyi Tan
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Jia Gu
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Yanjuan Liu
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Caiyan Li
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Gui Xiao
4   Department of Nursing, Hainan Medical University, Haikou, Hainan, China
,
Ke Liu
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Meidong Liu
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Sipin Tan
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Zihui Xiao
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Huali Zhang‡   **
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
,
Xianzhong Xiao‡   **
1   Key Laboratory of Sepsis Translational Medicine of Hunan, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
› Author Affiliations Funding This study is supported by the National Natural Science Fund of China (Grant No. 81671895, 81871610, 81471897, and 81870071) and the Natural Science Foundation of Hunan Province, China (Grant No. 2019JJ40393).
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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.

Keywords

heat shock factor 1 - sepsis - tissue-type plasminogen activator - coagulation - microthrombosis

* These authors contributed equally as first authors to the work.


** These authors contributed equally as corresponding authors to the work.




Publication History

Received: 30 August 2020

Accepted: 04 December 2020

Accepted Manuscript online:
09 December 2020

Article published online:
27 September 2021

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