{"title":"S -亚硝基谷胱甘肽还原酶作为啮齿动物糖尿病血管并发症的治疗靶点","authors":"Shuang Zhao, Tianyu Song, Xin Tang, Chenglin Fan, Yuhao Yang, Zhiren Zhang, Ying Xia, Yan Zhang, Jiawei Cao, Ziyu Wang, Zhiguang Shi, Xinlong Tang, Dongjin Wang, Guoyong Yin, Shaohua Zhang, Yuanqing Gao, Hongshan Chen, Liansheng Wang, Feng Chen, Hong Wang, Bo Yu, Yu Cao, Kangyun Sun, Xin Liu, Xiujie Wang, Chenghui Yan, Yaling Han, Yi Han, Liping Xie, Yong Ji","doi":"10.1126/scitranslmed.adn9216","DOIUrl":null,"url":null,"abstract":"<div >Endothelial dysfunction is one of the earliest processes in diabetes and a major contributor to diabetic vascular complications, which often exhibit limited response to glucose-lowering therapies. We identified up-regulated <i>S</i>-nitrosoglutathione reductase (GSNOR) as a critical factor associated with diabetic vascular complications by unbiased proteomics. Elevated GSNOR expression was observed in the endothelium of patients with type 2 diabetes and in streptozotocin (STZ)–induced type 1 diabetes mice as well as in <i>db/db</i> type 2 diabetes mouse models. Genetic ablation of endothelial <i>Gsnor</i> promoted angiogenesis, maintained vascular permeability, and improved vasodilation in type 1 diabetes mice induced by STZ. GSNOR deficiency protected against high glucose–induced endothelial dysfunction in vitro, as evidenced by rescued tube formation, enhanced spheroid sprouting, maintained barrier integrity, and reduced permeability. Mechanistically, GSNOR orchestrated endothelial dysfunction independently of its enzymatic activity by binding the transcription factor ETS-related gene (ERG) and triggered its nuclear export through chromosome region maintenance 1. We synthesized NYY-001, an oral agent, that selectively blocks the GSNOR-ERG interaction. The direct targeting of NYY-001 to GSNOR was determined by resolving the crystal structure of their complex using cryo–electron microscopy. NYY-001 treatment enhanced postischemic neovascularization and restored vascular permeability in the peripheral vasculature in STZ-induced type 1 diabetes and <i>db/db</i> type 2 diabetes mouse models. These findings reveal a mechanistic role for the GSNOR-ERG complex in diabetic vascular complications and highlight NYY-001 as a promising therapeutic candidate.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 818","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"S-nitrosoglutathione reductase as a therapeutic target for diabetic vascular complications in rodent models\",\"authors\":\"Shuang Zhao, Tianyu Song, Xin Tang, Chenglin Fan, Yuhao Yang, Zhiren Zhang, Ying Xia, Yan Zhang, Jiawei Cao, Ziyu Wang, Zhiguang Shi, Xinlong Tang, Dongjin Wang, Guoyong Yin, Shaohua Zhang, Yuanqing Gao, Hongshan Chen, Liansheng Wang, Feng Chen, Hong Wang, Bo Yu, Yu Cao, Kangyun Sun, Xin Liu, Xiujie Wang, Chenghui Yan, Yaling Han, Yi Han, Liping Xie, Yong Ji\",\"doi\":\"10.1126/scitranslmed.adn9216\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Endothelial dysfunction is one of the earliest processes in diabetes and a major contributor to diabetic vascular complications, which often exhibit limited response to glucose-lowering therapies. We identified up-regulated <i>S</i>-nitrosoglutathione reductase (GSNOR) as a critical factor associated with diabetic vascular complications by unbiased proteomics. Elevated GSNOR expression was observed in the endothelium of patients with type 2 diabetes and in streptozotocin (STZ)–induced type 1 diabetes mice as well as in <i>db/db</i> type 2 diabetes mouse models. Genetic ablation of endothelial <i>Gsnor</i> promoted angiogenesis, maintained vascular permeability, and improved vasodilation in type 1 diabetes mice induced by STZ. GSNOR deficiency protected against high glucose–induced endothelial dysfunction in vitro, as evidenced by rescued tube formation, enhanced spheroid sprouting, maintained barrier integrity, and reduced permeability. Mechanistically, GSNOR orchestrated endothelial dysfunction independently of its enzymatic activity by binding the transcription factor ETS-related gene (ERG) and triggered its nuclear export through chromosome region maintenance 1. We synthesized NYY-001, an oral agent, that selectively blocks the GSNOR-ERG interaction. The direct targeting of NYY-001 to GSNOR was determined by resolving the crystal structure of their complex using cryo–electron microscopy. NYY-001 treatment enhanced postischemic neovascularization and restored vascular permeability in the peripheral vasculature in STZ-induced type 1 diabetes and <i>db/db</i> type 2 diabetes mouse models. These findings reveal a mechanistic role for the GSNOR-ERG complex in diabetic vascular complications and highlight NYY-001 as a promising therapeutic candidate.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":\"17 818\",\"pages\":\"\"},\"PeriodicalIF\":14.6000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.adn9216\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adn9216","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
S-nitrosoglutathione reductase as a therapeutic target for diabetic vascular complications in rodent models
Endothelial dysfunction is one of the earliest processes in diabetes and a major contributor to diabetic vascular complications, which often exhibit limited response to glucose-lowering therapies. We identified up-regulated S-nitrosoglutathione reductase (GSNOR) as a critical factor associated with diabetic vascular complications by unbiased proteomics. Elevated GSNOR expression was observed in the endothelium of patients with type 2 diabetes and in streptozotocin (STZ)–induced type 1 diabetes mice as well as in db/db type 2 diabetes mouse models. Genetic ablation of endothelial Gsnor promoted angiogenesis, maintained vascular permeability, and improved vasodilation in type 1 diabetes mice induced by STZ. GSNOR deficiency protected against high glucose–induced endothelial dysfunction in vitro, as evidenced by rescued tube formation, enhanced spheroid sprouting, maintained barrier integrity, and reduced permeability. Mechanistically, GSNOR orchestrated endothelial dysfunction independently of its enzymatic activity by binding the transcription factor ETS-related gene (ERG) and triggered its nuclear export through chromosome region maintenance 1. We synthesized NYY-001, an oral agent, that selectively blocks the GSNOR-ERG interaction. The direct targeting of NYY-001 to GSNOR was determined by resolving the crystal structure of their complex using cryo–electron microscopy. NYY-001 treatment enhanced postischemic neovascularization and restored vascular permeability in the peripheral vasculature in STZ-induced type 1 diabetes and db/db type 2 diabetes mouse models. These findings reveal a mechanistic role for the GSNOR-ERG complex in diabetic vascular complications and highlight NYY-001 as a promising therapeutic candidate.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.