糖尿病患者 PCSK9 表达的增加会促进 VEGFR2 泛素化,从而抑制内皮功能和皮肤伤口愈合。

IF 8 2区 生物学 Q1 BIOLOGY
Science China Life Sciences Pub Date : 2024-12-01 Epub Date: 2024-08-15 DOI:10.1007/s11427-023-2688-8
Jian-Jun Gao, Fang-Yuan Wu, Yu-Jia Liu, Le Li, Yi-Jun Lin, Yue-Ting Kang, Yue-Ming Peng, Yi-Fang Liu, Chen Wang, Zhen-Sheng Ma, Yang Cao, Hong-Yu Cao, Zhi-Wei Mo, Yan Li, Jing-Song Ou, Zhi-Jun Ou
{"title":"糖尿病患者 PCSK9 表达的增加会促进 VEGFR2 泛素化,从而抑制内皮功能和皮肤伤口愈合。","authors":"Jian-Jun Gao, Fang-Yuan Wu, Yu-Jia Liu, Le Li, Yi-Jun Lin, Yue-Ting Kang, Yue-Ming Peng, Yi-Fang Liu, Chen Wang, Zhen-Sheng Ma, Yang Cao, Hong-Yu Cao, Zhi-Wei Mo, Yan Li, Jing-Song Ou, Zhi-Jun Ou","doi":"10.1007/s11427-023-2688-8","DOIUrl":null,"url":null,"abstract":"<p><p>Diabetic foot ulcers (DFUs) are a serious vascular disease. Currently, no effective methods are available for treating DFUs. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid levels to promote atherosclerosis. However, the role of PCSK9 in DFUs remains unclear. In this study, we found that the expression of PCSK9 in endothelial cells (ECs) increased significantly under high glucose (HG) stimulation and in diabetic plasma and vessels. Specifically, PCSK9 promotes the E3 ubiquitin-protein ligase NEDD4 binding to vascular endothelial growth factor receptor 2 (VEGFR2), which led to the ubiquitination of VEGFR2, resulting in its degradation and downregulation in ECs. Furthermore, PCSK9 suppresses the expression and activation of AKT, endothelial nitric oxide synthase (eNOS), and ERK1/2, leading to decreased nitric oxide (NO) production and increased superoxide anion (O<sub>2</sub><sup>._</sup>) generation, which impairs vascular endothelial function and angiogenesis. Importantly, using evolocumab to limit the increase in PCSK9 expression blocked the HG-induced inhibition of NO production and the increase in O<sub>2</sub><sup>._</sup> production, as well as inhibited the phosphorylation and expression of AKT, eNOS, and ERK1/2. Moreover, evolocumab improved vascular endothelial function and angiogenesis, and promoted wound healing in diabetes. Our findings suggest that targeting PCSK9 is a novel therapeutic approach for treating DFUs.</p>","PeriodicalId":21576,"journal":{"name":"Science China Life Sciences","volume":" ","pages":"2635-2649"},"PeriodicalIF":8.0000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Increase of PCSK9 expression in diabetes promotes VEGFR2 ubiquitination to inhibit endothelial function and skin wound healing.\",\"authors\":\"Jian-Jun Gao, Fang-Yuan Wu, Yu-Jia Liu, Le Li, Yi-Jun Lin, Yue-Ting Kang, Yue-Ming Peng, Yi-Fang Liu, Chen Wang, Zhen-Sheng Ma, Yang Cao, Hong-Yu Cao, Zhi-Wei Mo, Yan Li, Jing-Song Ou, Zhi-Jun Ou\",\"doi\":\"10.1007/s11427-023-2688-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Diabetic foot ulcers (DFUs) are a serious vascular disease. Currently, no effective methods are available for treating DFUs. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid levels to promote atherosclerosis. However, the role of PCSK9 in DFUs remains unclear. In this study, we found that the expression of PCSK9 in endothelial cells (ECs) increased significantly under high glucose (HG) stimulation and in diabetic plasma and vessels. Specifically, PCSK9 promotes the E3 ubiquitin-protein ligase NEDD4 binding to vascular endothelial growth factor receptor 2 (VEGFR2), which led to the ubiquitination of VEGFR2, resulting in its degradation and downregulation in ECs. Furthermore, PCSK9 suppresses the expression and activation of AKT, endothelial nitric oxide synthase (eNOS), and ERK1/2, leading to decreased nitric oxide (NO) production and increased superoxide anion (O<sub>2</sub><sup>._</sup>) generation, which impairs vascular endothelial function and angiogenesis. Importantly, using evolocumab to limit the increase in PCSK9 expression blocked the HG-induced inhibition of NO production and the increase in O<sub>2</sub><sup>._</sup> production, as well as inhibited the phosphorylation and expression of AKT, eNOS, and ERK1/2. Moreover, evolocumab improved vascular endothelial function and angiogenesis, and promoted wound healing in diabetes. Our findings suggest that targeting PCSK9 is a novel therapeutic approach for treating DFUs.</p>\",\"PeriodicalId\":21576,\"journal\":{\"name\":\"Science China Life Sciences\",\"volume\":\" \",\"pages\":\"2635-2649\"},\"PeriodicalIF\":8.0000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science China Life Sciences\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1007/s11427-023-2688-8\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/15 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science China Life Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s11427-023-2688-8","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/15 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

糖尿病足溃疡(DFU)是一种严重的血管疾病。目前,还没有治疗糖尿病足溃疡的有效方法。Pro-protein convertase subtilisin/kexin type 9(PCSK9)可调节血脂水平,促进动脉粥样硬化。然而,PCSK9在DFU中的作用仍不清楚。本研究发现,在高血糖(HG)刺激下,糖尿病血浆和血管中内皮细胞(ECs)中 PCSK9 的表达显著增加。具体而言,PCSK9可促进E3泛素蛋白连接酶NEDD4与血管内皮生长因子受体2(VEGFR2)结合,从而导致VEGFR2泛素化,导致其降解并在ECs中下调。此外,PCSK9 还能抑制 AKT、内皮一氧化氮合酶(eNOS)和 ERK1/2 的表达和活化,导致一氧化氮(NO)生成减少和超氧阴离子(O2._)生成增加,从而损害血管内皮功能和血管生成。重要的是,使用 evolocumab 限制 PCSK9 表达的增加可以阻止 HG 诱导的一氧化氮生成抑制和 O2._ 生成增加,并抑制 AKT、eNOS 和 ERK1/2 的磷酸化和表达。此外,evolocumab 还能改善血管内皮功能和血管生成,促进糖尿病患者的伤口愈合。我们的研究结果表明,靶向 PCSK9 是治疗 DFU 的一种新型治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Increase of PCSK9 expression in diabetes promotes VEGFR2 ubiquitination to inhibit endothelial function and skin wound healing.

Diabetic foot ulcers (DFUs) are a serious vascular disease. Currently, no effective methods are available for treating DFUs. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid levels to promote atherosclerosis. However, the role of PCSK9 in DFUs remains unclear. In this study, we found that the expression of PCSK9 in endothelial cells (ECs) increased significantly under high glucose (HG) stimulation and in diabetic plasma and vessels. Specifically, PCSK9 promotes the E3 ubiquitin-protein ligase NEDD4 binding to vascular endothelial growth factor receptor 2 (VEGFR2), which led to the ubiquitination of VEGFR2, resulting in its degradation and downregulation in ECs. Furthermore, PCSK9 suppresses the expression and activation of AKT, endothelial nitric oxide synthase (eNOS), and ERK1/2, leading to decreased nitric oxide (NO) production and increased superoxide anion (O2._) generation, which impairs vascular endothelial function and angiogenesis. Importantly, using evolocumab to limit the increase in PCSK9 expression blocked the HG-induced inhibition of NO production and the increase in O2._ production, as well as inhibited the phosphorylation and expression of AKT, eNOS, and ERK1/2. Moreover, evolocumab improved vascular endothelial function and angiogenesis, and promoted wound healing in diabetes. Our findings suggest that targeting PCSK9 is a novel therapeutic approach for treating DFUs.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
15.10
自引率
8.80%
发文量
2907
审稿时长
3.2 months
期刊介绍: Science China Life Sciences is a scholarly journal co-sponsored by the Chinese Academy of Sciences and the National Natural Science Foundation of China, and it is published by Science China Press. The journal is dedicated to publishing high-quality, original research findings in both basic and applied life science research.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信