Abstract
Defects in homeostatic regulation of cholesterol and fatty acids are associated with major cardiometabolic risk factors that are prevalent in type 2 diabetes and atherosclerotic cardiovascular disease. Regulatory input is found at many levels; however, recent findings have revealed pivotal roles for small non-coding RNAs (microRNAs) of the endogenous RNA interference pathway in post-transcriptional control of major regulatory mechanisms underpinning cholesterol and energy homeostasis. In addition, aberrant expression of microRNAs has been implicated in marked pathophysiologic events contributing to the progression and development of atherosclerosis, including loss of endothelial integrity, vascular smooth muscle cell proliferation, neointimal hyperplasia, and foam cell formation. This review surveys the impact of microRNA-mediated regulation in biological processes governing the cholesterol/lipoprotein metabolism, fatty acid β-oxidation (eg by miR-122 and miR-33), and endothelial dysfunction related to atherosclerosis. Given the current advances in microRNA-based technologies, the clinical potential of microRNAs as novel therapeutic targets is highlighted as new alternative strategies to ameliorate cardiometabolic diseases.
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References
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
Moller DE, Kaufman KD. Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med. 2005;56:45–62.
Small EM, Olson ER. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011;469(7330):336–42.
Corcoran DL, Pandit KV, et al. Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data. PLoS ONE. 2009;4(4):e5279.
Hafner M et al. Identification of microRNAs and other small regulatory RNAs using cDNA library sequencing. Methods. 2008;44(1):3–12.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.
Xu J, Li CX, et al. MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features. Nucleic Acids Res. 2011;39(3):825–36.
Alvarez-Saavedra E, Horvitz HR. Many families of C. elegans microRNAs are not essential for development or viability. Curr Biol. 2010;20(4):367–73.
Liu N, Olson EN. MicroRNA regulatory networks in cardiovascular development. Dev Cell. 2010;18(4):510–25.
•• Brenner JL, Jasiewicz KL, Fahley AF, Kemp BJ, Abbott AL. Loss of individual microRNAs causes mutant phenotypes in sensitized genetic backgrounds in C. elegans. Curr Biol. 2010;20(14):1321–5. This work provides significant evidence suggesting redundant roles of miRNAs in Caenorhabditis elegans.
Ambros V. MicroRNAs: genetically sensitized worms reveal new secrets. Curr Biol. 2010;20(14):R598–600.
Stenvang J, Lindow M, Kauppinen S. Targeting of microRNAs for therapeutics. Biochem Soc Trans. 2008;36(Pt 6):1197–200.
Krutzfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438:685–9.
Esau C et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006;3(2):87–98.
Elmén J, Lindow M, Schütz S, Lawrence M, et al. LNA-mediated microRNA silencing in non-human primates. Nature. 2008;452(7189):896–9.
Iliopoulos D, Drosatos K, Hiyama Y, Goldberg IJ, Zannis VI. MicroRNA-370 controls the expression of microRNA-122 and Cpt1alpha and affects lipid metabolism. J Lipid Res. 2010;51(6):1513–23.
Horton JD, Goldstein JL, Brown MS. SREBPs: transcriptional mediators of lipid homeostasis. Cold Spring Harb Symp Quant Biol. 2002;67:491–8.
Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89(3):331–40.
Puljak L, Parameswara V, Dolovcak S, et al. Evidence for AMPK-dependent regulation of exocytosis of lipoproteins in a model liver cell line. Exp Cell Res. 2008;314(10):2100–9.
Kim YW, Kim YM, et al. Inhibition of SREBP-1c-mediated hepatic steatosis and oxidative stress by sauchinone, an AMPK-activating lignan in Saururus chinensis. Free Radic Biol Med. 2010;48(4):567–78.
Walker AK et al. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 2010;24(13):1403–17.
Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 2000;14(22):2819–30.
•• Najafi-Shoushtari SH, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;328(5985):1566–9. This report shows co-operative expression and function of miR-33 and its SREBP host genes and underscores the promise of using LNA miR-33 antisense oligonucleotide to increase plasma HDL levels. This study helps establish miR-33a and miR-33b as regulators of cholesterol homeostasis.
•• Horie T, MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. Proc Natl Acad Sci USA. 2010;107(40):17321–6. This study provides the first evidence that genetic miR-33a deletion in mice leads to elevated levels of circulating HDL.
•• Rayner KJ, Suárez Y, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328(5985):1570–3 This study reports that miR-33a is regulated by cellular and dietary cholesterol and inhibits two members of the ABC transporter family, ABCA1 and ABCG1, which regulate cellular cholesterol efflux in mice. It helped establish miR-33 as a regulator of cholesterol homeostasis.
•• Gerin I, et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem. 2010;285(44):33652–61. This work, besides establishing the role of miR-33a in cellular cholesterol efflux, also indicates its involvement in regulating levels of free fatty acids and triacylglycerol in vitro.
•• Marquart TJ, Allen RM, Ory DS, Baldán A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci USA. 2010;107(27):12228–32. This study demonstrates that miR-33a repress the expression of cholesterol efflux pump ABCA1 by using an adenoviral-mediated miR-33a expression system and that antisense-oligonucleotide-targeting of miR-33a in mice increases plasma HDL levels.
Yasuda T, Ishida T, Rader DJ. Update on the role of endothelial lipase in high-density lipoprotein metabolism, reverse cholesterol transport, and atherosclerosis. Circ J. 2010;74(11):2263–70.
Ho PC, Chang KC, Chuang YS, Wei LN. Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production. FASEB J. 2011 Feb 1. [Epub ahead of print]
Chen JF, Murchison EP, Tang R, et al. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proc Natl Acad Sci USA. 2008;105(6):2111–6.
Albinsson S, Suarez Y, et al. MicroRNAs are necessary for vascular smooth muscle growth, differentiation, and function. Arterioscler Thromb Vasc Biol. 2010;30(6):1118–26.
Poliseno L, Tuccoli A, Mariani L, et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood. 2006;108(9):3068–71.
Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.
•• Minami Y, Satoh M, Maesawa C, et al. Effect of atorvastatin on microRNA 221/222 expression in endothelial progenitor cells obtained from patients with coronary artery disease. Eur J Clin Invest. 2009;39(5):359–67. This work shows that miRNA likely mediates beneficial cholesterol-lowering independent effects of statins.
Fish JE, Santoro MM, Morton SU, et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 2008;15(2):272–84.
•• Nicoli S, Standley C, Walker P, et al. MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature. 2010;464(7292):1196–200. This important article shows a crucial role for miR-126 in angiogenesis.
Zernecke A, Bidzhekov K, Noels H, et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal. 2009;2(100):ra81.
Inoue T, Node K. Molecular basis of restenosis and novel issues of drug-eluting stents. Circ J. 2009;73(4):615–21.
Cordes KR, Sheehy NT, White MP, et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460(7256):705–10.
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(12):1590–8.
Ji R, Cheng Y, Yue J, et al. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res. 2007;100(11):1579–88.
Zhang C. MicroRNA-145 in vascular smooth muscle cell biology: a new therapeutic target for vascular disease. Cell Cycle. 2009;8(21):3469–73.
Rader DJ, Puré E. Lipoproteins, macrophage function, and atherosclerosis: beyond the foam cell? Cell Metab. 2005;1(4):223–30.
•• Chen T, Huang Z, Wang L, et al. MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9 expression in oxLDL-stimulated monocyte/macrophages. Cardiovasc Res. 2009;83(1):131–9. Using a microarray-based analysis, this study shows that miR-125a-5p, among other microRNAs, can modulate oxLDL uptake and cytokine production in human monocyte/macrophages.
Huang RS, Hu GQ, Lin B, Lin ZY, Sun CC. MicroRNA-155 silencing enhances inflammatory response and lipid uptake in oxidized low-density lipoprotein-stimulated human THP-1 macrophages. J Investig Med. 2010;58(8):961–7.
•• Lanford RE, Hildebrandt-Eriksen ES, Petri A, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 2010;327(5962):198–201. This outstanding work shows the great potential of LNA-modified oligonucleotide as promising therapeutics. Injection of LNA miR-122 into non-human primates (chimpanzees) with HCV leads to long-lasting suppression of HCV viremia and shows, for the first time, the promise of anti-microRNA targeted therapy for the treatment of chronic diseases.
Taylor AJ. Evidence to support aggressive management of high-density lipoprotein cholesterol: implications of recent imaging trials. Am J Cardiol. 2008;101(8A):36B–43.
Chisholm JW, Hong J, Mills SA, Lawn RM. The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse. J Lipid Res. 2003;44(11):2039–48.
Tall AR et al. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab. 2008;7(5):365–75.
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S. Hani Najafi-Shoushtari reports no potential conflict of interest relevant to this article.
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Najafi-Shoushtari, S.H. MicroRNAs in Cardiometabolic Disease. Curr Atheroscler Rep 13, 202–207 (2011). https://doi.org/10.1007/s11883-011-0179-y
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DOI: https://doi.org/10.1007/s11883-011-0179-y