Inflammation-associated microRNA changes in circulating exosomes of heart failure patients

Abstract

ObjectiveMiR-486 and miR-146a are cardiomyocyte-enriched microRNAs that control cell survival and self-regulation of inflammation. These microRNAs are released into circulation and are detected in plasma or in circulating exosomes. Little is known whether heart failure affects their release into circulation, which this study investigated.ResultsTotal and exosome-specific microRNAs in plasma of 40 heart failure patients and 20 controls were prepared using the miRVana Kit. We measured exosomal and total plasma microRNAs separately because exosomes serve as cargos that transfer biological materials and alter signaling in distant organs, whereas microRNAs in plasma indicate the level of tissue damage and are mostly derived from dead cells. qRT-PCR was used to quantify miR-486, miR-146a, and miR-16. Heart failure did not significantly affect plasma miR-486/miR-16 and miR-146a/miR-16 ratio, although miR-146a/miR-16 showed a trend of elevated expression (2.3 ± 0.79, p = 0.27). By contrast, circulating exosomal miR-146a/miR-16 ratio was higher in heart failure patients (2.46 ± 0.51, p = 0.05). miR-146a is induced in response to inflammation as a part of inflammation attenuation circuitry. Indeed, Tnfα and Gm-csf increased miR-146a but not miR-486 in the cardiomyocyte cell line H9C2. These results, if confirmed in a larger study, may help to develop circulating exosomal miR-146a as a biomarker of heart failure.

Non-Exosomal and Exosomal Circulatory MicroRNAs: Which Are More Valid as Biomarkers?

“…Circulating miRNAs are unusually stable due to (1) their packaging in vesicles, such as in exosomes (Chugh et al, 2013) or apoptotic bodies, (2) their RNA folding and size, and/or (3) their presence in Ago-containing ribonucleic acid: protein (RNP) complexes (Chugh et al, 2013), with nucleophosmin (Kubiczkova et al, 2014), or with high-density lipoproteins (HDL) (Köberle et al, 2013;Fornari et al, 2015). The stability of miRNAs results from their resistance toward the action of ribonucleases (Jansen et al, 2014;Dinh et al, 2016;Beg et al, 2017;Liu et al, 2017a;Yokoi et al, 2017;de Candia et al, 2013;Li et al, 2012). This stability means that they are long-lived in biological fluids (Ragusa et al, 2015;Emanueli et al, 2016) and are therefore proposed as attractive diagnostic (Pirola et al, 2015) and prognostic biomarkers (Fornari et al, 2015).…”

“…The source of miRNAs being the cause of variation in results can be seen in a study reported by Huang et al (2017; tissues versus circulating miRNAs) and a study by Reithmair et al (2017; cellular versus vesicle or cell-free miRNAs). The second limitation is lacking a large sample size and validation of results in different independent cohorts (Gallo et al, 2012;Momen−Heravi et al, 2015;Dinh et al, 2016;Jansen et al, 2016;Beg et al, 2017;Huang et al, 2017;Khare et al, 2017;Liu et al, 2017a;Rabinowits et al, 2017;Yokoi et al, 2017). The sample size in biomarker studies is usually only suitable for a pilot study.…”

Various aspects of inflammation in heart failure

“…NF-kappaB increases the expression of miR-146a, which inhibits the action of the IL-1 and TNF-alpha receptors, thereby decreasing inflammation. For this reason, the cardioprotective effect of miR-146a has been highlighted recently [90]. Lately, a trend towards elevated plasma concentration of miR-146a and miR-486 has been demonstrated in a group of patients with HF when compared with a control group [90].…”

“…For this reason, the cardioprotective effect of miR-146a has been highlighted recently [90]. Lately, a trend towards elevated plasma concentration of miR-146a and miR-486 has been demonstrated in a group of patients with HF when compared with a control group [90]. In addition, NF-kappaB reduces the level of muscle-specific transcription factor (MyoD).…”

“…MyoD, together with myocardin-related transcription factor (MRTF), positively regulates the expression of miR-486. The balance between the activity of MRTF and MyoD in inflammatory conditions determines the level of miR-486 expression in the myocardium [90].…”