MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. (Nat Med. 2014;20(4):368-76.)

報告日期: 2014/11/25
報告時間: 3:10/4:00
報告學生: 許玲維(以英文報告)
講評老師: 呂佩融
附件下載: 下載[1443-1412238291-1.pdf] 

MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1

Andreas Schober et al., Nature Medicine. 2014; 20:368-376

Date: 2014.11.25

Place: Room 602

Speaker: Ling-Wei Hsu

Commentator: Dr. Pei-Jung Lu

Endothelium constructs by endothelial cells (ECs), is the first layer that contact to blood flow directly. Hemodynamic influence ECs functions by shear stress, particularly disturbed flow that happened at the site of arterial branches, result in endothelial injury that induce inflammation or apoptosis, and develop to atherosclerosis. The mechanisms of increasing EC turnover against injured arteries remains incompletely understood. Endothelial microRNAs have an important role in the response of vascular cells to hemodynamic stress. miR-126 is the most abundant miRNAs in ECs, and it was reported that it has vascular protection. The authors hypothesize miR-126 promotes the arterial EC regeneration, and prevents atherosclerotic lesion formation by regulating EC turnover. To determine the role of miR-126 in endothelial injuries, the authors used wire injury models in HCD-fed miR-126-/- Apoe-/- mice to mimic endothelial injury and atherosclerosis. They found that deficiency of miR-126 increased arterial lesion area and reduced ECs proliferation. Furthermore, they used TargetScan and MicroCosm Targets to search potential miR-126 target genes, and after microarray and RT-PCR analysis, they found Delta-like 1 homolog, Dlk1 is miR-126-5p’s target gene. They found that Dlk1 increased in injured endothelium of miR-126-/- Apoe-/- mice, and then they mutated Dlk1 3’UTR, used miR-126-5p mimic, LNA-126-5p and Dlk1 siRNA in HUVECs to confirm that Dlk1 is miR-126-5p’s target gene. In addition, lesion area increased, EC proliferation reduced and Dlk1 expression increased by locally perivascular treated miR-126-5p antagomir on injured arteries. Conversely, treated miR-126-5p mimic had opposite effects. The site of arterial branches, also named predilection (P) sites, easier to form atherosclerosis lesions, and the lesser curvature sites named nonpredilection (NP) sites. miR-126 deficiency exacerbated atherosclerosis at NP sites. Moreover, miR-126-5p expression was lower at P sites and higher at NP sites, but Dlk1 expression was oppositely. To study the effect of miR-126 in disturbed flow, the authors used partial ligation of the carotid artery model. They found that Dlk1 expression increased, and treatment of miR-126-5p mimic reduced lesion area and increased ECs proliferation in disturbed flow model. The authors used nanoparticle coated miR-126-5p mimic by interventricular injection to treat HCD-fed Apoe-/- mice, and the results were similar to other models. Higher miR-126-5p levels are atheroprotective in humans and that treatment with miR-126-5p mimics may have therapeutic value in human atherosclerosis.