Abstract 17596: Mir-126-5p Promotes Endothelial Cell Proliferation and Limits Lesion Formation During Atherosclerosis by Suppressing Dlk1
Endothelial cell (EC) function and survival are affected by hyperlipidemia and disturbed laminar flow, which in turn leads to atherosclerosis; endothelial miR-126-3p promotes angiogenesis and reduces atherosclerosis. We have previously reported that the passenger strand miR-126-5p reduces neointima formation by increasing EC proliferation through suppression of Dlk1 following endothelial denudation. Here we aimed to assess the role of the miR-126-5p/Dlk1 axis in EC proliferation during atherogenesis.
MiR-126-/-Apoe-/- and miR-126+/+Apoe-/- (control) mice were subjected to high cholesterol diet for 3 months. Lipid deposition quantified in Oil red O-stained thoraco-abdominal aortas was increased ~4-fold in miR-126-/-Apoe-/- mice (n = 12-16, p < 0.05). However, the aortic root lesion size was not significantly different between the groups (n = 11-12, p = ns). Expression of miR-126-5p, but not of miR-126-3p, was suppressed, whereas the Dlk1 expression was increased at the aortic root and predilection sites of atherosclerosis in Apoe-/- mice as detected by qRT-PCR (n = 3-5, p < 0.05). Moreover, acutely disturbed flow in partially ligated carotid arteries of Apoe-/- mice reduced miR-126-5p after 5 d and increased Dlk1 expression after 7 d (n = 3-4, p < 0.05). In contrast to aortic roots (n = 11-12, p = ns) and partially ligated arteries (n = 4-5, p = ns), EC proliferation was reduced by ~80% in carotid arteries of miR-126-/-Apoe-/- compared to miR-126+/+Apoe-/- mice (n = 9-10, p < 0.05) as determined by CD31/Ki67 immunostaining. In human atherosclerotic lesions (n = 22-27), miR-126-5p expression levels were negatively correlated with the endothelial DLK1 abundance (R2 = 0.2288) and EC proliferation (R2 = 0.5477). Systemic application of miR-126-5p mimics packaged in nanoparticles reduced lesion formation and enhanced EC proliferation in miR-126-/-Apoe-/- and miR-126+/+Apoe-/- mice as compared to control mimics (n = 4, p < 0.05).
In conclusion, the absence of the miR-126-5p strand is responsible for the exacerbated lesion formation at non-predilection sites in miR-126-/-Apoe-/- mice due to impaired EC proliferation. Increasing miR-126-5p levels by systemic treatment proposes to be a promising therapeutic strategy against atherosclerosis.
- © 2013 by American Heart Association, Inc.