Abstract MP10: The Long Non-coding RNA LINC02502 Modulates Vascular Smooth Muscle Cell Phenotypes

Abstract

Background: Genome-wide association studies led to the identification of several genomic loci associated with coronary artery disease risk. One such locus is chromosome 4q27 which harbors the long non-coding RNA (lncRNA) LINC02502 and the PDE5A gene. PDE5A encodes phosphodiesterase 5a, the enzyme that degrades the second messenger cyclic guanosine monophosphate. We previously showed that differential PDE5A expression is mediated via LINC02502 -mediated scaffolding of the transcription factor REST. Methods and Results: In a screening of vascular cell types, we identified vascular smooth muscle cells (VSMC) to express both PDE5A and LINC02502 . Using RNA interference, we studied the ability of VSMC to migrate in the presence or absence of LINC02502 in in vitro scratch wound healing assays. Knockdown of LINC02502 led to a significant reduction of VSMC migration. VSMC proliferation was determined using BrdU incorporation assays. After knockdown of LINC02502 , VSMC proliferation was decreased. To investigate whether LINC02502 influences inflammatory phenotypes, we ectopically overexpressed the lncRNA in VSMC and analyzed a panel of inflammatory transcripts using quantitative PCR. In general, overexpression of LINC02502 rendered VSMC more inflammatory. Particularly, LINC02502 increased the expression of interleukin-1β, chemokine (C-X-C motif) ligand 1, and fractalkine. Importantly, we did not make these observations secondary to overexpression of PDE5A, suggesting that LINC02502 regulates these transcripts in an independent manner. In silico analysis, however, revealed that LINC02502 -regulated targets were enriched for predicted targets of REST. Conclusion: The lncRNA LINC02502 is a candidate for mediating the risk of coronary artery disease at the chromosome 4q27 locus via regulating PDE5A . Independent of PDE5A regulation, LINC02502 promotes pro-atherosclerotic phenotypes in VSMC, i.e., migration, proliferation, and expression of inflammatory transcripts. Modulating LINC02502 might be a novel approach to prevent and treat coronary atherosclerosis via multiple pathways.