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Thromb Haemost. 2014 Oct;112(4):796-802. doi: 10.1160/TH13-11-0905. Epub 2014 Jul 10.

MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr-/-mice.

Author information

1
Carlos Fernández-Hernando, Yale University School of Medicine, 522 10 Amistad Street, Amistad Research Building, Room 337c, New Haven, CT 06510, USA, Tel.: +1 203 737 4615, Fax: +1 203 737 2290, E-mail: carlos.fernandez@yale.edu.
2
Giuseppe Danilo Norata, Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy, Tel.: +39 02 50318313, Fax: +39 02 50318386, E-mail: danilo.norata@unimi.it.

Abstract

The miR-143/145 cluster regulates VSMC specific gene expression, thus controlling differentiation, plasticity and contractile function, and promoting the VSMC phenotypic switch from a contractile/non-proliferative to a migrating/proliferative state. More recently increased miR-145 expression was observed in human carotid atherosclerotic plaques from symptomatic patients. The goal of this study was to investigate the contribution of miR-143/145 during atherogenesis by generating mice lacking miR-143/145 on an Ldlr-deficient background. Ldlr-/- and Ldlr-/--miR-143/145-/- (DKO) were fed a Western diet (WD) for 16 weeks. At the end of the treatment, the lipid profile and the atherosclerotic lesions were assessed in both groups of mice. Absence of miR-143/145 significantly reduced atherosclerotic plaque size and macrophage infiltration. Plasma total cholesterol levels were lower in DKO and FLPC analysis showed decreased cholesterol content in VLDL and LDL fractions. Interestingly miR-143/145 deficiency per se resulted in increased hepatic and vascular ABCA1 expression. We further confirmed the direct regulation of miR-145 on ABCA1 expression by qRT-PCR, Western blotting and 3'UTR-luciferase reporter assays. In summary, miR-143/145 deficiency significantly reduces atherosclerosis in mice. Therapeutic inhibition of miR-145 might be useful for treating atherosclerotic vascular disease.

KEYWORDS:

ABCA1; atherosclerosis; miR-143/145; smooth muscle cells

PMID:
25008143
PMCID:
PMC4180777
DOI:
10.1160/TH13-11-0905
[Indexed for MEDLINE]
Free PMC Article

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