MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins
Kasey C Vickers, Brian T Palmisano, Bassem M Shoucri, Robert D Shamburek, Alan T Remaley, Kasey C Vickers, Brian T Palmisano, Bassem M Shoucri, Robert D Shamburek, Alan T Remaley
Abstract
Circulating microRNAs (miRNA) are relatively stable in plasma and are a new class of disease biomarkers. Here we present evidence that high-density lipoprotein (HDL) transports endogenous miRNAs and delivers them to recipient cells with functional targeting capabilities. Cellular export of miRNAs to HDL was demonstrated to be regulated by neutral sphingomyelinase. Reconstituted HDL injected into mice retrieved distinct miRNA profiles from normal and atherogenic models. HDL delivery of both exogenous and endogenous miRNAs resulted in the direct targeting of messenger RNA reporters. Furthermore, HDL-mediated delivery of miRNAs to recipient cells was demonstrated to be dependent on scavenger receptor class B type I. The human HDL-miRNA profile of normal subjects is significantly different from that of familial hypercholesterolemia subjects. Notably, HDL-miRNA from atherosclerotic subjects induced differential gene expression, with significant loss of conserved mRNA targets in cultured hepatocytes. Collectively, these observations indicate that HDL participates in a mechanism of intercellular communication involving the transport and delivery of miRNAs.
Conflict of interest statement
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
© 2011 Macmillan Publishers Limited. All rights reserved
Figures
References
- Simons M, Raposo G. Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21:575–581.
- Valadi H, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–659.
- Hunter MP, et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One. 2008;3:e3694.
- Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia. 2006;20:1487–1495.
- Selbach M, et al. Widespread changes in protein synthesis induced by microRNAs. Nature. 2008;455:58–63.
- Baek D, et al. The impact of microRNAs on protein output. Nature. 2008;455:64–71.
- Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–297.
- Mitchell PS, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105:10513–10518.
- Janas T, Janas T, Yarus M. Specific RNA binding to ordered phospholipid bilayers. Nucleic Acids Res. 2006;34:2128–2136.
- Manavbasi Y, Suleymanoglu E. Nucleic acid-phospholipid recognition: Fourier transform infrared spectrometric characterization of ternary phospholipid-inorganic cation-DNA complex and its relevance to chemicopharmaceutical design of nanometric liposome based gene delivery formulations. Arch Pharm Res. 2007;30:1027–1040.
- Suleymanoglu E. Phospholipid-nucleic acid recognition: developing an immobilized liposome chromatography for DNA separation and analysis. PDA J Pharm Sci Technol. 2006;60:232–239.
- Gromelski S, Brezesinski G. DNA condensation and interaction with zwitterionic phospholipids mediated by divalent cations. Langmuir. 2006;22:6293–6301.
- Kim SI, et al. Systemic and specific delivery of small interfering RNAs to the liver mediated by apolipoprotein A-I. Mol Ther. 2007;15:1145–1152.
- McManus JJ, Radler JO, Dawson KA. Does Calcium Turn a Zwitterionic Lipid Cationic? The Journal of Physical Chemistry B. 2003;107:9869–9875.
- Mengistu DH, Bohinc K, May S. Binding of DNA to zwitterionic lipid layers mediated by divalent cations. J Phys Chem B. 2009;113:12277–12282.
- Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3(Unit 3):22.
- Lima ES, Maranhao RC. Rapid, Simple Laser-Light-Scattering Method for HDL Particle Sizing in Whole Plasma. Clin Chem. 2004;50:1086–1088.
- Simpson RJ, Lim JW, Moritz RL, Mathivanan S. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics. 2009;6:267–283.
- Mathivanan S, Simpson RJ. ExoCarta: A compendium of exosomal proteins and RNA. Proteomics. 2009;9:4997–5000.
- Conde-Vancells J, et al. Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. J Proteome Res. 2008;7:5157–5166.
- Lim LP, Glasner ME, Yekta S, Burge CB, Bartel DP. Vertebrate microRNA genes. Science. 2003;299:1540.
- Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83–86.
- Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111:1795–1803.
- Lund-Katz S, Phillips MC. High density lipoprotein structure-function and role in reverse cholesterol transport. Subcell Biochem. 2010;51:183–227.
- Kosaka N, et al. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010;285:17442–17452.
- Sun G, Li H, Rossi JJ. Sequence context outside the target region influences the effectiveness of miR-223 target sites in the RhoB 3′UTR. Nucleic Acids Res. 2010;38:239–252.
- Cui XD, et al. EFNA1 ligand and its receptor EphA2: potential biomarkers for hepatocellular carcinoma. Int J Cancer. 2010;126:940–949.
- Feinberg EH, Hunter CP. Transport of dsRNA into cells by the transmembrane protein SID-1. Science. 2003;301:1545–1547.
- Wolfrum C, et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat Biotechnol. 2007;25:1149–1157.
- Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.
- Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19:92–105.
- Podrez EA. Antioxidant Properties of High Density Lipoprotein and Atherosclerosis. Clin Exp Pharmacol Physiol. 2010;37:719–725.
- Heinecke JW. The HDL proteome: a marker--and perhaps mediator--of coronary artery disease. J Lipid Res. 2009;50 (Suppl):S167–171.
- Rothblat GH, Phillips MC. High-density lipoprotein heterogeneity and function in reverse cholesterol transport. Curr Opin Lipidol. 2010;21:229–238.
- Lu D, Rhodes DG. Binding of phosphorothioate oligonucleotides to zwitterionic liposomes. Biochim Biophys Acta. 2002;1563:45–52.
- Qiu X, et al. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat Struct Mol Biol. 2007;14:106–113.
- Trajkovic K, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–1247.
- Ferracin M, Veronese A, Negrini M. Micromarkers: miRNAs in cancer diagnosis and prognosis. Expert Rev Mol Diagn. 2010;10:297–308.
- Wang GK, et al. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J. 2010;31:659–666.
- Wang JF, et al. Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem Biophys Res Commun. 2010;394:184–188.
- Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Kerin MJ. MicroRNAs as Novel Biomarkers for Breast Cancer. J Oncol. 2009;2009:950201.
- Gilad S, et al. Serum microRNAs are promising novel biomarkers. PLoS One. 2008;3:e3148.
- MacArthur JM, et al. Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members. J Clin Invest. 2007;117:153–164.
- Ramakrishnan SN, Lau P, Burke LJ, Muscat GE. Rev-erbbeta regulates the expression of genes involved in lipid absorption in skeletal muscle cells: evidence for cross-talk between orphan nuclear receptors and myokines. J Biol Chem. 2005;280:8651–8659.
- Yao Y, et al. High-density lipoproteins affect endothelial BMP-signaling by modulating expression of the activin-like kinase receptor 1 and 2. Arterioscler Thromb Vasc Biol. 2008;28:2266–2274.
- Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V. Neovascularization in human atherosclerosis. Circulation. 2006;113:2245–2252.
- Lee H, et al. Hepatic siRNA delivery using recombinant human apolipoprotein AI in mice. Biochem Biophys Res Commun. 2009;378:192–196.
- Fukao T, et al. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell. 2007;129:617–631.
- Gentner B, et al. Stable knockdown of microRNA in vivo by lentiviral vectors. Nat Methods. 2009;6:63–66.
- Eyholzer M, et al. Complexity of miR-223 regulation by CEBPA in human AML. Leuk Res. 2010;34:672–676.
- Fazi F, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell. 2005;123:819–831.
- Pulikkan JA, et al. Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia. Blood. 2010;115:1768–1778.
- Lu H, Buchan RJ, Cook SA. MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism. Cardiovasc Res. 2010;86:410–420.
- Yu CH, Xu CF, Li YM. Association of MicroRNA-223 expression with hepatic ischemia/reperfusion injury in mice. Dig Dis Sci. 2009;54:2362–2366.
- Sugatani T, Hruska KA. MicroRNA-223 is a key factor in osteoclast differentiation. J Cell Biochem. 2007;101:996–999.
- Iida H, et al. Ephrin-A1 expression contributes to the malignant characteristics of {alpha}-fetoprotein producing hepatocellular carcinoma. Gut. 2005;54:843–851.
- Huang L, et al. Immunoaffinity separation of plasma proteins by IgY microbeads: meeting the needs of proteomic sample preparation and analysis. Proteomics. 2005;5:3314–3328.
- Nieuwland R, et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood. 2000;95:930–935.
- Matz CE, Jonas A. Micellar complexes of human apolipoprotein A-I with phosphatidylcholines and cholesterol prepared from cholate-lipid dispersions. J Biol Chem. 1982;257:4535–4540.
- Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 2008;36:D154–158.
- Cline MS, et al. Integration of biological networks and gene expression data using Cytoscape. Nat Protoc. 2007;2:2366–2382.
- Li C, Wong WH. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci U S A. 2001;98:31–36.
Source: PubMed