Thromb Haemost 2014; 112(04): 796-802
DOI: 10.1160/TH13-11-0905
Animal Models
Schattauer GmbH

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

Federica Sala
1  Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
,
Juan F. Aranda
2  Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
3  Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
,
Noemi Rotllan
2  Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
3  Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
,
Cristina M. Ramírez
2  Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
3  Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
,
Binod Aryal
2  Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
3  Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
,
Leonardo Elia
4  Fondazione Humanitas per la Ricerca, Rozzano, Italy
5  IRCCS Multimedica, Milan, Italy
,
Gianluigi Condorelli
4  Fondazione Humanitas per la Ricerca, Rozzano, Italy
,
Alberico Luigi Catapano
5  IRCCS Multimedica, Milan, Italy
,
Carlos Fernández-Hernando
2  Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA
3  Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
,
Giuseppe Danilo Norata
1  Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
6  Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy
7  The Blizard Institute, Centre for Diabetes, Barts and The London School of Medicine & Dentistry, Queen Mary University, London, UK
› Author Affiliations
Further Information

Publication History

Received: 04 November 2013

Accepted after major revision: 14 May 2014

Publication Date:
21 November 2017 (online)

Summary

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.