miR‐210 as a therapeutic target in diabetes‐associated endothelial dysfunction

内皮功能障碍 氧化应激 转基因小鼠 内分泌学 内科学 内皮 转基因 糖尿病 基因剔除小鼠 生物 一氧化氮 细胞生物学 医学 基因 生物化学 受体
作者
Aida Collado,Tong Jiao,Eftychia Kontidou,Lucas Rannier Ribeiro Antonino Carvalho,Ekaterina Chernogubova,Jiangning Yang,Germana Zaccagnini,Allan Z. Zhao,John Tengbom,Xiaowei Zheng,Bence Réthi,Michael Alvarsson,Sergiu‐Bogdan Catrina,Ali Mahdi,Mattias Carlström,Fabio Martelli,John Pernow,Zhichao Zhou
出处
期刊:British Journal of Pharmacology [Wiley]
被引量:3
标识
DOI:10.1111/bph.17329
摘要

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.

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