LncRNA MIR181A1HG Deficiency Attenuates Vascular Inflammation and Atherosclerosis

Endothelial cell (EC) dysfunction and vascular inflammation are critical in the initiation and progression of atherosclerosis. Long noncoding RNAs play a critical role in vascular pathology, but relatively little is known about their involvement in controlling vascular inflammation. MIR181A1HG is a conserved long noncoding RNA located in juxtaposition with miR-181a1 and miR-181b1, both involved in vascular inflammation. The study aims to investigate the role of MIR181A1HG in regulating vascular inflammation. We examined the expression of MIR181A1HG in both human and mouse atherosclerotic lesions. Loss-of-function and gain-of-function studies, and multiple RNA-protein interaction assays were used to investigate the role and molecular mechanisms of MIR181A1HG in vascular inflammation and atherosclerosis. The atherosclerotic phenotypes of MIR181A1HG-/-ApoE-/- mice were analyzed in combination with single-cell RNA sequencing. The transcriptional regulation of MIR181A1HG was verified through luciferase reporter and chromatin immunoprecipitation assays. MIR181A1HG expression was abundant in ECs and significantly increased in both human and mouse atherosclerotic lesions. MIR181A1HG-/-ApoE-/- mice had reduced NLRP (NLR family pyrin domain containing) 3 inflammasome signaling, EC activation, monocyte infiltration, and atherosclerotic lesion formation. Genetic deletion of MIR181A1HG in myeloid sells did not alter the progression of atherosclerosis. Single-cell RNA sequencing analysis revealed that MIR181A1HG deficiency reduced the proportion of immune cells and enriched anti-inflammation pathways in EC clusters in atherosclerotic lesions. In contrast, EC-specific MIR181A1HG overexpression promoted NLRP3 inflammasome signaling, EC activation, and atherosclerotic lesion formation, effects that were reversed by pharmacological inhibition of NLRP3 (MCC950). MIR181A1HG was transcriptionally activated via an NF-κB (nuclear factor kappa B)/p65-dependent pathway. Mechanistically, MIR181A1HG mediated these effects on regulating NLRP3 inflammasome and EC activation in part through decoying Foxp1 (forkhead box transcription factor 1) away from the promoters of target genes, which was independent of the miR-181a1/b1 cluster. Finally, EC-specific Foxp1 silencing reversed the antiatherosclerotic effect mediated by MIR181A1HG-deletion in vivo. These findings identify MIR181A1HG as a central driver of vascular inflammation in atherosclerosis by its ability to decoy Foxp1 away from target gene promoters and activate NLRP3 inflammasome in the vascular endothelium. Our study suggests MIR181A1HG as a future therapeutic target for vascular inflammatory disease states.