Role of lncRNA Snhg18 in diabetes-induced macrophage dysfunction and atherosclerosis

Project: Research

Investigators

  • Rituparna Ganguly (PI)

Description

Vascular complication of diabetes is extensively controlled by epigenetic mechanisms including long non-coding RNAs (lncRNAs). Here we investigated role of lncRNAs in hyperglycemia-induced macrophage dysfunction and accelerated atherosclerosis. RNAseq analysis on bone marrow macrophages derived from Streptozotocin-induced diabetic (STZ-Apoe-/-) vs. control atherosclerotic Apoe-/-(Con-Apoe-/-) mice revealed 154 dysregulated lncRNAs among which, one of the robustly upregulated candidates was small nucleolar RNA host gene 18 (Snhg18) located on mouse chromosome (Chr) 15.Snhg18was upregulated in diabetic vs control-Apoe-/-aortic tissue, type 2 diabeticdb/dbvs control db/+ mice peritoneal macrophages and high glucose (HG) induced mouse RAW macrophages. A human ortholog ofSNHG18located on Chr5 was significantly increased in high glucose (HG; 25mM) treated THP1 monocytes. RNAseq was performed on Apoe-/-BMDMs afterdsiRNAknockdown ofSnhg18in presence or absence of HG. Data analysis showed thatSnhg18knockdown inhibited a repertoire of HG-induced fibroticgenes(Col1a1, Col1a2, Serpine1, Fn1)associated with extracellular matrix interaction, cell adhesion and migration pathways which may lead to increased macrophage adhesion, migration, vascular fibrosis, and atherosclerosis development. Cellular fractionation and RT-qPCR showed pan cellular localization ofSnhg18. Bioinformatics analysis predicted thatSNHG18has conserved binding sites for microRNAs miR-143, 218, 17, 26 and 144, which can potentially target these HG-induced fibrotic genes (Col1a1, Col1a2, Serpine1, Fn1). Based on these, we hypothesize that lncRNASnhg18acts as a competing endogenous (ceRNA) RNA for specific anti-fibrotic microRNAs, resulting in increased vascular fibrosis and atherosclerosis development in diabetes. Therefore, in this proposal,Snhg18will be investigated for its functional roles, ceRNA mechanisms, regulation and therapeutic relevance in diabetes-induced macrophage dysfunction and atherogenesis. Overall, this study will uncover new lncRNA-based epigenetic mechanisms in diabetic atherosclerotic disease and instigate future lncRNA-based therapies.
Award amount$106,532.00
Award date01/01/2019
Program typePostdoctoral Fellowship
Award ID19POST34380488
Effective start/end date01/01/201903/30/2020
StatusFinished