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Hyperglycemia inhibition of endothelial miR-140-3p mediates angiogenic dysfunction in diabetes mellitus.

Abstract：

OBJECTIVE:MicroRNAs (miRNAs) have emerged as promising regulators of diabetes mellitus (DM)-induced angiogenic dysfunction in endothelial cells (ECs), but information vis-à-vis the functional roles of distinct miRNAs remain surprisingly scarce. The current study was designed to elucidate the expression and function of miR-140-3p in diabetic ECs. METHODS:miR-140-3p expression was evaluated in DM mouse model and in human ECs using RT-qPCR, Northern blot and RNA fluorescent in situ hybridization. Effects of miR-140-3p manipulation on ECs function were evaluated using cell proliferation, migration and in vitro tube formation assay. Regulation of FOXK2 transcription by miR-140-3p was determined by luciferase reporter assay and site-directed mutagenesis. RESULTS:miR-140-3p expression was significantly down-regulated in high glucose-challenged ECs. Under normal conditions, miR-140-3p knockdown impaired endothelial proliferation and migration, and endothelial tube formation. Mechanistically, miR-140-3p exhibited its proangiogenic effects through directly inhibiting the expression of the forkhead transcription factor FOXK2. From a therapeutic standpoint, shRNA-mediated stable inhibition of FOXK2 effectively corrected miR-140-3p deficiency-induced impairment of ECs proliferation and in vitro angiogenesis. CONCLUSION:Endothelial miR-140-3p positive regulates ECs function by directly targeting FOXK2 signaling. Deregulation of miR-140-3p/FOXK2 cascade by hyperglycemia thus serves as an important contributor to angiogenic dysfunction in DM.

journal_name

J Diabetes Complications

journal_title

Journal of diabetes and its complications

authors

Wang D,Wang H,Liu C,Mu X,Cheng S

doi

10.1016/j.jdiacomp.2019.02.001

subject

Has Abstract

pub_date

2019-05-01 00:00:00

pages

374-382

issue

5

eissn

1056-8727

issn

1873-460X

pii

S1056-8727(18)30962-0

journal_volume

33

pub_type

杂志文章

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