S-nitrosoglutathione reductase as a therapeutic target for diabetic vascular complications in rodent models

IF 14.6 1区 医学 Q1 CELL BIOLOGY
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
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Abstract

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.
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
内皮功能障碍是糖尿病的早期过程之一,也是糖尿病血管并发症的主要原因之一,这些并发症通常对降糖治疗反应有限。通过无偏倚蛋白质组学,我们发现上调的S -亚硝基谷胱甘肽还原酶(GSNOR)是与糖尿病血管并发症相关的一个关键因素。在2型糖尿病患者、STZ诱导的1型糖尿病小鼠和db/db 2型糖尿病小鼠模型的内皮中观察到GSNOR表达升高。STZ诱导的1型糖尿病小鼠,基因消融内皮Gsnor促进血管生成,维持血管通透性,改善血管舒张。GSNOR缺乏对高糖诱导的体外内皮功能障碍有保护作用,这可以通过挽救管形成、增强球状萌芽、维持屏障完整性和降低通透性来证明。从机制上讲,GSNOR通过结合转录因子ets相关基因(ERG)独立于酶活性调控内皮功能障碍,并通过染色体区域维持触发其核输出1。我们合成了NYY-001,一种口服药物,选择性阻断gsnorr - erg相互作用。通过低温电镜分析其配合物的晶体结构,确定了NYY-001对GSNOR的直接靶向性。在stz诱导的1型糖尿病和db/db 2型糖尿病小鼠模型中,NYY-001治疗增强了缺血后新生血管的形成,并恢复了外周血管的通透性。这些发现揭示了gsnr - erg复合物在糖尿病血管并发症中的机制作用,并强调NYY-001是一种有希望的治疗候选者。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
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.
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