Dysregulation of MicroRNA Regulatory Network in Lower Extremities Arterial Disease

Anna Bogucka-Kocka; Daniel P Zalewski; Karol P Ruszel; Andrzej Stępniewski; Dariusz Gałkowski; Jacek Bogucki; Łukasz Komsta; Przemysław Kołodziej; Tomasz Zubilewicz; Marcin Feldo; Janusz Kocki

doi:10.3389/fgene.2019.01200

Dysregulation of MicroRNA Regulatory Network in Lower Extremities Arterial Disease

Front Genet. 2019 Nov 22:10:1200. doi: 10.3389/fgene.2019.01200. eCollection 2019.

Affiliations

¹ Chair and Department of Biology and Genetics, Medical University of Lublin, Lublin, Poland.
² Department of Clinical Genetics, Chair of Medical Genetics, Medical University of Lublin, Lublin, Poland.
³ Ecotech Complex, Analytical and Programme Centre for Advanced Environmentally-Friendly Technologies, University of Marie Curie-Sklodowska, Lublin, Poland.
⁴ Department of Pathology and Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States.
⁵ Chair and Department of Medicinal Chemistry, Medical University of Lublin, Lublin, Poland.
⁶ Department of Vascular Surgery and Angiology, Medical University of Lublin, Lublin, Poland.

Abstract

Atherosclerosis and its comorbidities are the major contributors to the global burden of death worldwide. Lower extremities arterial disease (LEAD) is a common manifestation of atherosclerotic disease of arteries of lower extremities. MicroRNAs belong to epigenetic factors that regulate gene expression and have not yet been extensively studied in LEAD. We aimed to indicate the most promising microRNA and gene expression signatures of LEAD, to identify interactions between microRNA and genes and to describe potential effect of modulated gene expression. High-throughput sequencing was employed to examine microRNAome and transcriptome of peripheral blood mononuclear cells of patients with LEAD, in relation to controls. Statistical significance of microRNAs and genes analysis results was evaluated using DESeq2 and uninformative variable elimination by partial least squares methods. Altered expression of 26 microRNAs (hsa-let-7f-1-3p, hsa-miR-34a-5p, -122-5p, -3591-3p, -34a-3p, -1261, -21-5p, -15a-5p, -548d-5p, -34b-5p, -424-3p, -548aa, -548t-3p, -4423-3p, -196a-5p, -330-3p, -766-3p, -30e-3p, -125b-5p, -1301-3p, -3184-5p, -423-3p, -339-3p, -138-5p, -99a-3p, and -6087) and 14 genes (AK5, CD248, CDS2, FAM129A, FBLN2, GGT1, NOG, NRCAM, PDE7A, RP11-545E17.3, SLC12A2, SLC16A10, SLC4A10, and ZSCAN18) were the most significantly differentially expressed in LEAD group compared to controls. Discriminative value of revealed microRNAs and genes were confirmed by receiver operating characteristic analysis. Dysregulations of 26 microRNAs and 14 genes were used to propose novel biomarkers of LEAD. Regulatory interactions between biomarker microRNAs and genes were studied in silico using R multiMiR package. Functional analysis of genes modulated by proposed biomarker microRNAs was performed using DAVID 6.8 tools and revealed terms closely related to atherosclerosis and, interestingly, the processes involving nervous system. The study provides new insight into microRNA-dependent regulatory mechanisms involved in pathology of LEAD. Proposed microRNA and gene biomarkers of LEAD may provide new diagnostic and therapeutic opportunities.

Keywords: atherosclerosis; biomarker; gene expression; low extremities arterial disease; miRNA; miRNA expression; miRNA regulation; microRNA.

Associated data

figshare/10.6084/m9.figshare.9918773.v3