The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-05-23 DOI:10.1242/dmm.052145
Victor S Tapia, Sarah E Withers, Ran Zhou, Abigail Bennington, Christopher Hoyle, Frances Hedley, Adam El Khouja, Nadim Luka, Marco Massimo, Siobhan Crilly, Katherine R Long, Catherine B Lawrence, Paul R Kasher
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引用次数: 0

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.

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25-羟基胆固醇在与感染和胆固醇失调相关的脑血管功能障碍病理生理学中的作用。
抗病毒酶胆固醇25-羟化酶(CH25H)及其代谢产物25-羟基胆固醇(25HC)在感染期间调节胆固醇代谢,与血管病理有关。病毒感染与脑出血(ICH)风险有关,但通过抗病毒反应导致脑出血的分子机制尚不清楚。我们假设在感染相关性脑出血的情况下,CH25H/25HC通路影响神经内皮的完整性。利用严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)刺突蛋白诱导的斑马鱼脑出血模型和含有微出血的胎儿人SARS-CoV-2相关皮质组织,我们发现CH25H在感染相关脑出血中上调。使用斑马鱼模型和人脑内皮细胞,我们询问25HC是否通过调节胆固醇代谢促进神经血管功能障碍。我们发现25HC和药理抑制胆固醇合成对斑马鱼脑出血和体外神经内皮功能障碍有叠加效应。在体外补充胆固醇也可挽救hc诱导的功能障碍。这些结果表明25HC可以通过重塑胆固醇代谢来失调脑内皮功能。我们认为CH25H/25HC在脑出血感染和胆固醇失调相关的脑血管功能障碍的病理生理中起重要作用。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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