Circulating miRNAs: Messengers on the Move
miRNAs are not intracellularly confined; indeed, they are remarkably stable in the extracellular space being detected in various physiological fluids of the human body, such as plasma and breast milk (Mitchell et al. 2008; Kosaka et al. 2010a; Weber et al. 2010). Variation on the miRNA profile in circulation has been described in numerous diseases, including cardiovascular diseases and cancer (Etheridge et al. 2011; Fichtlscherer et al. 2011; Creemers et al. 2012). miRNAs even in an unprocessed form do exist in the cell enclosed in vesicles such as microvesicles, exo- somes, or apoptotic bodies or are released building a complex with other molecules such as Argonaute proteins or nucleophosmin1 (NPM1) or associated with high- density lipoproteins (HDL) (Fig. 1.1) (Kosaka et al. 2010b; Vickers and Remaley 2012; Arroyo et al. 2011a). Arroyo et al. have demonstrated that vesicle-associated miRNAs represent a minority in the circulation, whereas the majority of miRNAs are present in a non-membrane-bound form (Arroyo et al. 2011b). Some miRNAs can become enriched in secretory vesicles, such as exosomes and apoptotic bodies, through sequence-specific interactions with RNA-binding proteins that regulate the loading into exosomes (Villarroya-Beltri et al. 2013; Zernecke et al. 2009). Similar to secreted proteins, miRNAs released from cells can mediate communication with remote cells. For instance, the atheroprotective laminar flow increases Klf2 levels triggering the release of miR-143 and miR-145 from ECs in microvesicles, which are taken up by neighboring smooth muscle cells (SMC) mediated thereby a beneficial contractile SMC phenotype (Hergenreider et al. 2012).