{"title":"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","authors":"Chengkun Kou, Xu Zhao, Xin Fan, Runmin Sun, Wenting Wang, Miaomiao Qi, Lulu Zhu, Xin Lin, Jing Yu","doi":"10.1111/cns.70210","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aims</h3>\n \n <p>We aimed to investigate the role of Rnf40 in hypertension-induced cerebrovascular endothelial barrier dysfunction and cognitive impairment.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Our findings suggest that increased Rnf40 levels exacerbate hypertension-induced cerebrovascular endothelial barrier dysfunction by ubiquitinating Parkin.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707429/pdf/","citationCount":"0","resultStr":"{\"title\":\"Rnf40 Exacerbates Hypertension-Induced Cerebrovascular Endothelial Barrier Dysfunction by Ubiquitination and Degradation of Parkin\",\"authors\":\"Chengkun Kou, Xu Zhao, Xin Fan, Runmin Sun, Wenting Wang, Miaomiao Qi, Lulu Zhu, Xin Lin, Jing Yu\",\"doi\":\"10.1111/cns.70210\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Aims</h3>\\n \\n <p>We aimed to investigate the role of Rnf40 in hypertension-induced cerebrovascular endothelial barrier dysfunction and cognitive impairment.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>Our findings suggest that increased Rnf40 levels exacerbate hypertension-induced cerebrovascular endothelial barrier dysfunction by ubiquitinating Parkin.</p>\\n </section>\\n </div>\",\"PeriodicalId\":154,\"journal\":{\"name\":\"CNS Neuroscience & Therapeutics\",\"volume\":\"31 1\",\"pages\":\"\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2025-01-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707429/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CNS Neuroscience & Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cns.70210\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70210","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Rnf40 Exacerbates Hypertension-Induced Cerebrovascular Endothelial Barrier Dysfunction by Ubiquitination and Degradation of Parkin
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.
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.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
