PUBLICATION
The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation
- Authors
- Tapia, V.S., Withers, S.E., Zhou, R., Bennington, A., Hoyle, C., Hedley, F., El Khouja, A., Luka, N., Massimo, M., Crilly, S., Long, K.R., Lawrence, C.B., Kasher, P.R.
- ID
- ZDB-PUB-250524-1
- Date
- 2025
- Source
- Disease models & mechanisms 18: (Journal)
- Registered Authors
- Kasher, Paul
- Keywords
- 25-hydroxycholesterol, Brain endothelium, Cholesterol, Intracerebral haemorrhage, SARS-CoV-2, Zebrafish
- MeSH Terms
-
- Humans
- Hydroxycholesterols*/metabolism
- Hydroxycholesterols*/pharmacology
- COVID-19*/complications
- COVID-19*/pathology
- COVID-19*/physiopathology
- COVID-19*/virology
- SARS-CoV-2/physiology
- Brain*/blood supply
- Brain*/pathology
- Brain*/physiopathology
- Steroid Hydroxylases/metabolism
- Animals
- Cholesterol*/metabolism
- Disease Models, Animal
- Zebrafish
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- PubMed
- 40406995 Full text @ Dis. Model. Mech.
Citation
Tapia, V.S., Withers, S.E., Zhou, R., Bennington, A., Hoyle, C., Hedley, F., El Khouja, A., Luka, N., Massimo, M., Crilly, S., Long, K.R., Lawrence, C.B., Kasher, P.R. (2025) The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation. Disease models & mechanisms. 18:.
Abstract
The antiviral enzyme cholesterol 25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC), which modulates cholesterol metabolism during infection, have been associated with vascular pathology. Viral infections have been linked to intracerebral haemorrhage (ICH) risk, but the molecular mechanisms leading to ICH via antiviral responses remain unknown. We hypothesised that the CH25H/25HC pathway impacts neuroendothelial integrity in the context of infection-associated ICH. Using a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-induced zebrafish ICH model and foetal human SARS-CoV-2-associated cortical tissue containing microbleeds, we identified upregulation of CH25H in infection-associated cerebral haemorrhage. Using zebrafish models and human brain endothelial cells, we asked whether 25HC promotes neurovascular dysfunction by modulating cholesterol metabolism. We found that 25HC and pharmacological inhibition of cholesterol synthesis had an additive effect to exacerbate brain bleeding in zebrafish and in vitro neuroendothelial dysfunction. 25HC-induced dysfunction was also rescued by cholesterol supplementation in vitro. These results demonstrate that 25HC can dysregulate brain endothelial function by remodelling cholesterol metabolism. We propose that CH25H/25HC plays an important role in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation in the context of ICH.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping