Hyperglycemia Determines Increased Specific MicroRNAs Levels in Sera and HDL of Acute Coronary Syndrome Patients and Stimulates MicroRNAs Production in Human Macrophages.

Natalia Simionescu,Doina R Dimulescu,Maya Simionescu,Loredan S Niculescu,Mihaela G Carnuta,Adelina Vlad,Camelia S Stancu,Anca V Sima,Mihaela R Popescu,Gabriela M Sanda,Andreea C Popescu,Partha Mukhopadhyay

doi:10.1371/journal.pone.0161201

Abstract

We aimed to determine the levels of microRNAs (miRNAs) in sera and HDL of acute coronary syndrome (ACS) compared to stable angina (SA) patients with/without hyperglycemia, and evaluate comparatively the functional effect of these sera on the processing machinery proteins (Drosha, DGCR8, Dicer) and miRNAs production in human macrophages. MiRNAs levels in sera and HDL from 35 SA and 72 ACS patients and 30 healthy subjects were measured by using microRNA TaqMan assays. MiR-223, miR-92a, miR-486, miR-122, miR-125a and miR-146a levels were higher in the hyperglycemic ACS compared to normoglycemic sera. MiR-223 and miR-486 prevailed in HDL2, while miR-92a predominated in HDL3, all three miRNAs discriminating between ACS and SA patients; their levels were increased in HDL from hyperglycemic ACS patients versus normoglycemic ones. The incubation of human macrophages with sera from ACS and SA patients showed that all patients’ sera induced an increase of Drosha, DGCR8 and Dicer expressions and of selected miRNAs levels compared to control sera, the effect being higher in the case of hyperglycemic versus normoglycemic ACS sera. The addition of glucose to SA and ACS sera increased Drosha, DGCR8 and Dicer expression and miRNAs levels in the exposed macrophages. In conclusion, hyperglycemia is associated with increased miR-223, miR-92a, miR-486 levels in HDL, which discriminate between ACS and SA patients. Exposure of human macrophages to ACS compared to SA sera determines the upregulation of Drosha, DGCR8 and Dicer expression and the increase of selected miRNAs production, the effect being augmented by an increased glucose concentration.

Highlights

MicroRNAs are small non-coding RNAs that act as gene regulators by inhibiting translation [1, 2]
The clinical data, serum lipids, apolipoproteins levels and paraoxonase 1 (PON1) activity of the hyperglycemic (HG) coronary artery disease (CAD) patients, compared to the normoglycemic (NG) ones are presented in Tables 1 and 2
Hyperglycemia was associated with significantly lower high density Lp (HDL)-C levels and PON1 activity (p

Summary

Introduction

MicroRNAs (miRNAs) are small non-coding RNAs that act as gene regulators by inhibiting translation [1, 2]. MiRNAs are transcribed by RNA polymerase II as pri-miRNAs [3] and are further processed to pre-miRNAs by the microprocessor complex comprised of the RNase III enzyme Drosha bound by its regulatory subunit DGCR8 [4, 5]. The pre-miRNAs are transported to the cytoplasm by Exportin-5 [6], where they are cleaved to miRNA duplex intermediates by the RNase III enzyme, Dicer [7]. MiRNAs can be exported outside the cells, circulate in the blood associated with microparticles, exosomes, lipoproteins (Lp) or protein complexes and act as long-distance extracellular messengers [8,9,10,11]. Modified cellular expression of miRNAs or altered circulating miRNAs profiles have been associated with several diseases, including atherosclerosis, obesity, diabetes and coronary artery disease [12,13,14,15,16]

Objectives

Methods

Results

Conclusion