Rnf40 Exacerbates Hypertension-Induced Cerebrovascular Endothelial Barrier Dysfunction by Ubiquitination and Degradation of Parkin

IF 4.8 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2025-01-08 DOI:10.1111/cns.70210

Chengkun Kou, Xu Zhao, Xin Fan, Runmin Sun, Wenting Wang, Miaomiao Qi, Lulu Zhu, Xin Lin, Jing Yu

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Abstract

Aims

We aimed to investigate the role of Rnf40 in hypertension-induced cerebrovascular endothelial barrier dysfunction and cognitive impairment.

Methods

We employed microarray data analysis and integrated bioinformatics databases to identify a novel E3 ligase, Rnf40, that targets Parkin. To understand the role of RNF40 in hypertension-induced cerebrovascular endothelial cell damage, we used pAAV-hFLT1-MCS-EGFP-3×Flag-mir30shRnf40 to establish an Rnf40-deficient model in spontaneously hypertensive rats (SHRs). We also evaluated the cerebrovascular endothelial barrier function, cerebral blood flow, and cognitive performance.

Results

We observed reduced mitophagy in cerebrovascular endothelial cells of SHRs compared with that in Wistar-Kyoto rats. Rnf40 facilitated K48-linked polyubiquitination and degradation of Parkin, thereby inhibiting mitophagy. In the Rnf40-deficient SHR model, knocking down Rnf40 restored mitophagy in cerebrovascular endothelial cells. Additionally, levels of tight junction proteins and cerebrovascular endothelial barrier function improved following Rnf40 downregulation. Rnf40 depletion also improved global cognitive performance and restored cerebral blood flow in SHRs.

Conclusion

Our findings suggest that increased Rnf40 levels exacerbate hypertension-induced cerebrovascular endothelial barrier dysfunction by ubiquitinating Parkin.

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Rnf40通过泛素化和Parkin降解加剧高血压诱导的脑血管内皮屏障功能障碍

目的：探讨Rnf40在高血压性脑血管内皮屏障功能障碍和认知功能障碍中的作用。方法：采用微阵列数据分析和集成生物信息学数据库鉴定了一种新的E3连接酶Rnf40，该酶靶向Parkin。为了了解RNF40在高血压诱导的脑血管内皮细胞损伤中的作用，我们利用pAAV-hFLT1-MCS-EGFP-3×Flag-mir30shRnf40建立自发性高血压大鼠（SHRs） RNF40缺失模型。我们还评估了脑血管内皮屏障功能、脑血流量和认知能力。结果：与Wistar-Kyoto大鼠相比，我们观察到SHRs脑血管内皮细胞的线粒体自噬减少。Rnf40促进k48相关的多泛素化和Parkin降解，从而抑制线粒体自噬。在Rnf40缺陷SHR模型中，敲低Rnf40可恢复脑血管内皮细胞的有丝分裂。此外，Rnf40下调后，紧密连接蛋白水平和脑血管内皮屏障功能得到改善。Rnf40缺失也改善了SHRs的整体认知能力并恢复了脑血流量。结论：Rnf40水平升高通过泛素化Parkin加剧高血压引起的脑血管内皮屏障功能障碍。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.