부산대학교 도서관

Introduction: Diabetes-associated atherosclerosis is characterized by excessive vascular wall inflammation, including impaired lipid deposition, increased immune cell infiltration and plaque formation in the vessel wall. Macrophages are instrumental for lesion formation, however the mechanisms underlying their impaired functional capacity remain poorly understood in diabetes. Herein, we identify a unique role of a macrophage-enriched lncRNA MERRICAL (Macrophage Enriched lncRNA Regulates Inflammation, Chemotaxis, and AtheroscLerosis) in the development of diabetes-associated atherosclerosis.Methods: Transcriptomic analysis of the aortic intima from Ldlr mice was performed at 4 time points along the continuum of lesion progression and regression under a high fat, high sucrose-containing (HFSC) or chow diet, respectively, to identify differentially expressed lncRNAs. Gain- and loss-of-function cell-based assays, RNA-protein interactions, and in vivo knockdown were performed to uncover the role of a top lncRNA candidate.Results: LncRNA MERRICAL is nuclear localized and increased by 249% in intimal lesions during progression. Transcriptomic analysis of MERRICAL-deficient bone marrow-derived macrophages showed decreased chemokine and inflammatory gene expression for Ccl3, Ccl4, and Il1β, with reduced chemotaxis and inflammatory-associated gene ontology pathways. Gain- and loss-of-function studies demonstrated the role of lncRNA MERRICAL in cis-regulation of its neighboring genes Ccl3 and Ccl4, an effect that is mediated in part via interaction with the histone modification enzyme H3K4me3. Remarkably, systemic knockdown of MERRICAL in HFSC-fed mice strongly reduced lesion formation by 73% in the aortic sinus by inhibiting the pro-inflammatory and Ccl3- and Ccl4-associated chemotactic response and decreasing the recruitment of leukocytes into the aortic wall.Conclusions: These findings establish a cis-regulatory mechanism by which a macrophage-specific lncRNA, MERRICAL, potently inhibits pro-inflammatory and chemotactic responses to alleviate lesion progression in diabetes, with implications for a broad range of diabetes-associated vascular disease states.