miR-210 as a therapeutic target in diabetes-associated endothelial dysfunction.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Aida Collado, Tong Jiao, Eftychia Kontidou, Lucas Rannier Ribeiro Antonino Carvalho, Ekaterina Chernogubova, Jiangning Yang, Germana Zaccagnini, Allan Zhao, John Tengbom, Xiaowei Zheng, Bence Rethi, Michael Alvarsson, Sergiu-Bogdan Catrina, Ali Mahdi, Mattias Carlström, Fabio Martelli, John Pernow, Zhichao Zhou
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Abstract

Background and purpose: MicroRNA (miR)-210 function in endothelial cells and its role in diabetes-associated endothelial dysfunction are not fully understood. We aimed to characterize the miR-210 function in endothelial cells and study its therapeutic potential in diabetes.

Experimental approach: Two different diabetic mouse models (db/db and Western diet-induced), miR-210 knockout and transgenic mice, isolated vessels and human endothelial cells were used.

Key results: miR-210 levels were lower in aortas isolated from db/db than in control mice. Endothelium-dependent relaxation (EDR) was impaired in aortas from miR-210 knockout mice, and this was restored by inhibiting miR-210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR-210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR-210. However, plasma miR-210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR-210 transgenic mice and pharmacological overexpression using miR-210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR-210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR-210 mimic restored decreased nitric oxide production by high glucose in endothelial cells.

Conclusion and implications: This study unravels the mechanisms by which down-regulated miR-210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR-210 serves as a novel therapeutic target.

miR-210 作为糖尿病相关内皮功能障碍的治疗靶点。
背景和目的:微RNA(miR)-210在内皮细胞中的功能及其在糖尿病相关内皮功能障碍中的作用尚未完全清楚。我们旨在描述 miR-210 在内皮细胞中的功能,并研究其在糖尿病中的治疗潜力:实验方法:使用两种不同的糖尿病小鼠模型(db/db 和西方饮食诱导型)、miR-210 基因敲除和转基因小鼠、离体血管和人类内皮细胞。通过抑制 miR-210 下游蛋白酪氨酸磷酸酶 1B (PTP1B)、线粒体甘油-3-磷酸脱氢酶 2 (GPD2)和线粒体氧化应激,内皮依赖性松弛(EDR)在 miR-210 基因敲除小鼠的主动脉中受损。抑制这些通路也能改善两种糖尿病小鼠模型的 EDR。高血糖会降低内皮细胞中的 miR-210 水平,并损害小鼠主动脉的 EDR,而过表达 miR-210 则可逆转这种影响。然而,血糖状况改善后,2 型糖尿病(T2D)患者的血浆 miR-210 水平并不受影响。值得注意的是,利用 miR-210 转基因小鼠进行基因过表达,以及利用 miR-210 体内模拟物进行药理过表达,可通过降低 PTP1B、GPD2 和氧化应激,改善两种糖尿病小鼠模型的内皮功能障碍。基因过表达 miR-210 改变了主动脉转录组,减少了氧化应激通路中的基因:本研究揭示了高糖下调 miR-210 导致 T2D 内皮功能障碍的机制,并证明 miR-210 是一种新型治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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