Subscribe to RSS
HSF1 alleviates microthrombosis and multiple organ dysfunction in mice with sepsisHSF1 alleviates microthrombosis and multiple organ dysfunction in mice with sepsis by upregulating the transcription of tissue–type plasminogen activator
Sepsis is a life-threatening complication of infection and is closely associated with coagulation abnormalities. Heat shock factor 1 (HSF1) is an important transcription factor involved in heat shock response and other biological processes. However, whether HSF1 plays regulatory roles in blood coagulation is still unclear. In this study, a sepsis model was generated in HSF1-knockout mice using caecal ligation and puncture, and the role of HSF1 in microthrombosis and multiple organ dysfunction was evaluated. Notably, lung, liver, and kidney tissues were significantly damaged, fibrin/fibrinogen deposition in the lungs and kidneys was increased, and coagulation activity was gradually increased over time in mice with sepsis; these changes were more obvious in HSF-/- mice than in HSF1+/+ mice. RNA-seq analysis of lung tissues showed that tissue-type plasminogen activator (t-PA) was upregulated in septic mice and was significantly lower in HSF1-knockout mice than in wild-type mice. The effects of HSF1 on t-PA expression were further validated in HSF1-knockout mice with sepsis and in bEnd.3 mouse brain microvascular endothelial cells in vitro using HSF1 RNA interference or overexpression under lipopolysaccharide stimulation. Bioinformatics analysis of the t-PA promoter sequence, combined with electromobility shift and luciferase reporter assays, showed that HSF1 directly up-regulated t-PA at the transcriptional level. Therefore, our results revealed, for the first time, that HSF1 suppressed coagulation activity and microthrombosis by directly up-regulating t-PA, thereby playing a protective role against multiple organ dysfunction in sepsis.
Received: 30 August 2020
Accepted after revision: 04 December 2020
09 December 2020 (online)
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany