THU0006 ASSOCIATION BETWEEN ALTERED MICRORNA EXPRESSION AND ARTERIAL WALL REMODELING IN GIANT CELL ARTERITIS

Abstract

Background:Immunopathology of giant cell arteritis (GCA) results from dysregulated interactions between arterial wall-resident non-immune cells, e.g. vascular smooth muscle cells (VSMCs), and components of the immune system [1]. In spite of several efforts at identifying microRNAs (miRNAs) implicated in the pathogenesis of GCA, the overall information on miRNA involvement in GCA and its related arterial fibro-sclerotic alterations remains scarce.Objectives:To analyze miRNA expression and identify target genes of dysregulated miRNAs in temporal arteries from GCA patients, and to determine their association with GCA-associated arterial wall remodeling.Methods:The study included formalin-fixed, paraffin-embedded temporal artery biopsies (TABs) from 71 clinically diagnosed treatment-naïve patients fulfilling the ACR 1990 classification criteria, and 22 non-GCA subjects (control group). Of GCA patients, 54 histologically positive and 17 histologically negative TABs were included. miRNA expression profiling was performed with quantitative real-time PCR (qPCR)-based miRNA PCR panels and qPCR. The miRDB database and STRING protein-protein network analysis were used for identification of miRNA gene targets and their pathway enrichment analysis, respectively.Results:Of 356 detected miRNAs, we determined significant under-expression of 78 and significant over-expression of 22 miRNAs (≥ 2-fold; p < 0.05) in TAB-positive GCA arteries compared to non-GCA controls, pointing to a strong dysregulation of miRNA expression in inflamed GCA arteries. Several dysregulated miRNAs targeted genes involved in the ubiquitin-proteasome system and the RNA silencing complex, suggesting a novel role of these pathways in GCA. qPCR validation confirmed a 1.9–14.2-fold (p < 0.001) over-expression of “pro-synthetic” (miR-21-3p/-21-5p/-146a-5p/-146b-5p/-424-5p) and 3.4–9.4-fold (p < 0.001) under-expression of “pro-contractile” (miR-23b-3p/-125a-5p/-143-3p/-143-5p/-145-3p/-145-5p/-195-5p/-365a-3p) VSMC phenotype-associated regulatory miRNAs in TAB-positive GCA arteries. These miRNAs targeted gene pathways involved in the arterial remodeling and regulation of the immune system, and their expression significantly correlated with the extent of intimal hyperplasia in TABs from GCA patients (p ≤ 0.015). Additionally, the expression of miR-21-3p/-21-5p/-146a-5p/-146b-5p/-365a-3p differentiated TAB-negative GCA arteries from non-GCA temporal arteries, making these miRNAs potential biomarkers of GCA.Conclusion:Our study demonstrated an extensive dysregulation of arterial miRNA networks in GCA, favoring the pathogenic switch in the VSMC phenotype and associated intimal hyperplasia. We identified several miRNAs, which could represent potential novel GCA biomarkers. Furthermore, our results imply that the ubiquitin-proteasome system and the RNA silencing complex are targets of dysregulated arterial miRNA networks in GCA lesions, providing new insight into the complexity of GCA pathogenesis.