Supplementary_MaterialsR2_Final_Clean.pdf (443.47 kB)
Download file

Downregulation of Erythrocyte miR-210 Induces Endothelial Dysfunction in Type 2 Diabetes

Download (443.47 kB)
figure
posted on 09.11.2021, 04:06 by Zhichao Zhou, Aida Collado, Changyan Sun, Yahor Tratsiakovich, Ali Mahdi, Hanna Winter, Ekaterina Chernogubova, Till Seime, Sampath Narayanan, Tong Jiao, Hong Jin, Michael Alvarsson, Xiaowei Zheng, Jiangning Yang, Ulf Hedin, Sergiu-Bogdan Catrina, Lars Maegdefessel, John Pernow
Red blood cells (RBCs) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBCs were co-incubated with arteries and endothelial cells ex vivo and transfused in vivo to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBCs from patients with T2DM (T2DM RBC) and diabetic rodents induced endothelial dysfunction ex vivo and in vivo. miR-210 levels were lower in human T2DM RBC than in RBCs from healthy subjects (H RBC). Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in H RBC or RBCs from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in non-diabetic patients. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBCs via downregulating vascular PTP1B and oxidative stress in diabetic mice in vivo. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM.

Funding

Diabetes Research Wellness Foundation 720-1519-16 and 363-PG EFSD/Sanofi European Diabetes Research Programme in Macrovascular Complications Hjärt-Lungfonden 20190266, 20190341 and 20200326 Karolinska Institute Grant 2018-018372018, 2020-01473 and 2020-02285 Lars Hiertas Minne Foundation FO2018-0156 Loo and Hans Ostermans Foundation 2018-01213 and 2020-01209 Sigurt and Elsa Goljes Memorial Foundation LA2017-0131 Stockholm County Council ALF 20190031 Strategic Research Program in Diabetes Swedish Research Council 2020-01372 and 013-66-104153-33 the Konung Gustaf V:s och Drottning Victorias Frimurarestifelse von Kantzow Foundation

History