MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins

A Corrigendum to this article was published on 23 December 2014

This article has been updated

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.

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Figure 1: HDL–RNA analysis.
Figure 2: Human HDL carries distinct miRNA signatures in health and disease.
Figure 3: The role of LDL and the LDLR in HDL–miRNA signatures.
Figure 4: HDL readily incorporates with miRNAs in vitro and in vivo.
Figure 5: HDL transfers miRNAs to recipient cells with functional targeting.
Figure 6: HDL–miRNA delivery is SR-BI-dependent.
Figure 7: Atherosclerotic HDL induces differential gene expression through miRNA transfer.

Change history

  • 08 December 2014

    In the version of this Article originally published online, incorrect values appearing in Supplementary Table S4 were used to generate Fig. 3a and to calculate the P and R values. The annotation between Exosome and HDL should have read ‘R = 0.22*’, the annotation between Exosome and LDL should have read ‘R = 0.63**’ and the annotation between HDL and LDL should have read ‘R = 0.54**’, where **P < 0.0001 and *P < 0.001. These errors have been corrected in the online versions of the Article, and in the Supplementary Information.

  • 23 December 2014

    Nat. Cell Biol. 13, 423–433 (2011); published online 20 March 2011; corrected after print 8 December 2014 In the version of this Article originally published online, incorrect values appearing in Supplementary Table S4 were used to generate Fig. 3a and to calculate the P and R values. The annotationbetween Exosome and HDL should have read 'R = 0.

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Acknowledgements

This study was helped by the NHLBI Electron Microscopy Core, Genomics Core and Proteomics Core Facilities. Special thanks are extended to P. Sethupathy, PhD, for target prediction and discussion, M. Sampson for her work on patient lipid profiles and A. Loncarich for statistical analysis. This research was supported in total by the Intramural Research Program of the NIH, NHLBI DIR.

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K.C.V., B.T.P. and A.T.R. designed the research plan and study. K.C.V., B.T.P. and B.M.S. carried out all experiments. R.D.S. provided human samples. K.C.V. and A.T.R. drafted and edited the manuscript.

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Correspondence to Kasey C. Vickers.

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Vickers, K., Palmisano, B., Shoucri, B. et al. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13, 423–433 (2011). https://doi.org/10.1038/ncb2210

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