Subscribe to RSS
MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr-/- mice
04 November 2013
Accepted after major revision: 14 May 2014
21 November 2017 (online)
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.
- 1 Albinsson S, Sessa WC. Can microRNAs control vascular smooth muscle phenotypic modulation and the response to injury?. Physiological Genom 2011; 43: 529-533.
- 2 Albinsson S, Skoura A, Yu J. et al. Smooth muscle miRNAs are critical for post-natal regulation of blood pressure and vascular function. PloS one 2011; 6: e18869.
- 3 Albinsson S, Suarez Y, Skoura A. et al. MicroRNAs are necessary for vascular smooth muscle growth, differentiation, and function. Arterioscl Thromb Vasc Biol 2010; 30: 1118-1126.
- 4 Norata GD, Sala F, Catapano AL. et al. MicroRNAs and lipoproteins: a connection beyond atherosclerosis?. Atherosclerosis 2013; 227: 209-215.
- 5 Cordes KR, Sheehy NT, White MP. et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 2009; 460: 705-710.
- 6 Elia L, Quintavalle M, Zhang J. et al. The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ 2009; 16: 1590-1598.
- 7 Xin M, Small EM, Sutherland LB. et al. MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes Dev 2009; 23: 2166-2178.
- 8 Boettger T, Beetz N, Kostin S. et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J Clin Invest 2009; 119: 2634-2647.
- 9 Hergenreider E, Heydt S, Treguer K. et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nature Cell Biol 2012; 14: 249-256.
- 10 Rader DJ, Parmacek MS. Secreted miRNAs suppress atherogenesis. Nature Cell Biol 2012; 14: 233-235.
- 11 Norata GD, Pinna C, Zappella F. et al. MicroRNA 143-145 deficiency impairs vascular function. Int J Immunopathol Pharmacol 2012; 25: 467-474.
- 12 Cipollone F, Felicioni L, Sarzani R. et al. A unique microRNA signature associated with plaque instability in humans. Stroke 2011; 42: 2556-2563.
- 13 Norata GD, Venu VK, Callegari E. et al. Effect of Tie-2 conditional deletion of BDNF on atherosclerosis in the ApoE null mutant mouse. Biochim Biophys Acta 2012; 1822: 927-935.
- 14 Shimizu-Hirota R, Sasamura H, Kuroda M. et al. Extracellular matrix glycoprotein biglycan enhances vascular smooth muscle cell proliferation and migration. Circulation Res 2004; 94: 1067-1074.
- 15 Jordan SD, Kruger M, Willmes DM. et al. Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nature Cell Biol 2011; 13: 434-446.
- 16 Lovren F, Pan Y, Quan A. et al. MicroRNA-145 targeted therapy reduces atherosclerosis. Circulation 2012; 126 (11) (Suppl. 01) S81-90.
- 17 Kang MH, Zhang LH, Wijesekara N. et al. Regulation of ABCA1 protein expression and function in hepatic and pancreatic islet cells by miR-145. Arterioscler Thromb Vasc Biol 2013; 33: 2724-2732.
- 18 Rong JX, Shapiro M, Trogan E. et al. Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc Natl Acad Sci USA 2003; 100: 13531-13536.
- 19 Esau C, Kang X, Peralta E. et al. MicroRNA-143 regulates adipocyte differentiation. J Biol Chem 2004; 279: 52361-52365.
- 20 Norata GD, Tibolla G, Catapano AL. Gene silencing approaches for the management of dyslipidaemia. Trends Pharmacol Sci 2013; 34: 198-205.
- 21 Norata GD, Ballantyne CM, Catapano AL. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs. Eur Heart J 2013; 34: 1783-1789.