Metabolic Syndrome Is Associated With Altered mRNA and miRNA Content in Human Circulating Extracellular Vesicles

Abstract

As mediators of intercellular communication, circulating extracellular vehicles (EVs) can modulate tissue and cellular pathways by altering transcription profiles in recipient cells, and their content may reflect the status of their parent cells. However, whether their cargo is altered in the metabolic syndrome (Mets) remains unclear. We hypothesized that MetS altered mRNAs and miRNAs packed within circulating-EVs. EVs were collected from plasma of patients with MetS or age-matched Lean controls (n=4 each). RNA sequencing was performed to identify dysregulated mRNAs and miRNAs, and analyze genes targeted by miRNAs, top pathways, and diseases associated with MetS-EVs. MetS patients showed elevated body weight, blood pressure, glucose, insulin, and liver injury markers levels. 1,446 mRNAs were downregulated and 32 upregulated in MetS- compared to Lean-EVs, whereas 40 miRNAs were selectively enriched and 10 downregulated in MetS-EVs. MetS upregulated in EVs genes involved in apoptosis, mitochondrial regulation, transport, and lipoproteins, but downregulated vessel and heart development, protein complex biogenesis, and angiogenesis. MetS also upregulated miRNAs targeting genes implicated in cellular processes, including oxidation-reduction, and downregulated miRNAs capable of modulating catalytic activity, as well as heart, blood vessel, and skeletal development, transcriptional regulation, apoptosis, and cell cycle. Our study, thus, indicates that human subjects with MetS show modified cargo of circulating EVs, which in turn may modulate several critical cellular functions and fate. These EVs may reflect the anomalous status of their parent cells, and potentially serve as important regulators, biomarkers, and targets in the progression and treatment of MetS.

Keywords: RNA sequencing; circulation; extracellular vehicles; extracellular vesicles; metabolic syndrome.