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

Autor: Collado A; Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Jiao T; Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Kontidou E; Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Carvalho LRRA; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Chernogubova E; Division of Cardiovascular Medicine, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Yang J; Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Zaccagnini G; Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy., Zhao A; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Tengbom J; Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Zheng X; Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Rethi B; Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Alvarsson M; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Catrina SB; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Centrum for Diabetes, Academic Specialist Centrum, Stockholm, Sweden., Mahdi A; Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden., Carlström M; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Martelli F; Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy., Pernow J; Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden., Zhou Z; Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2025 Jan; Vol. 182 (2), pp. 417-431. Date of Electronic Publication: 2024 Oct 14.
DOI: 10.1111/bph.17329
Abstrakt: 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.
Linked Articles: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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