302MiR-126-5p promotes endothelial cell proliferation and limits lesion formation during atherosclerosis by suppressing Dlk1

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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.

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