Endothelial cell-specific deletion of a microRNA accelerates atherosclerosis. (June 2022)

• Record Type: Journal Article
• Authors: Yang, Dafeng; Haemmig, Stefan; Chen, Jingshu; McCoy, Michael; Cheng, Henry S.; Zhou, Haoyang; Pérez-Cremades, Daniel; Cheng, Xiao; Sun, Xinghui; Haneo-Mejia, Jorge; Vellarikkal, Shamsudheen K.; Gupta, Rajat M.; Barrera, Victor; Feinberg, Mark W.
• Is Part Of: Atherosclerosis. Volume 350(2022)
• Page Start: 9
• Page End: 18
• Publication Date: 2022-06
• Subjects: Atherosclerosis -- Endothelial cells -- microRNA-181b; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2022.04.010
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Chronic vascular endothelial inflammation predisposes to atherosclerosis; however, the cell-autonomous roles for endothelial-expressing microRNAs (miRNAs) are poorly understood in this process. MiR-181b is expressed in several cellular constituents relevant to lesion formation. The aim of this study is to examine the role of genetic deficiency of the miR-181b locus in endothelial cells during atherogenesis. Methods and Results: Using a proprotein convertase subtilisin/kexin type 9 (PCSK9)-induced atherosclerosis mouse model, we demonstrated that endothelial cell (EC)-specific deletion of miR-181a2b2 significantly promoted atherosclerotic lesion formation, cell adhesion molecule expression, and the influx of lesional macrophages in the vessel wall. Yet, endothelium deletion of miR-181a2b2 did not affect body weight, lipid metabolism, anti-inflammatory Ly6C low or the pro-inflammatory Ly6C interm and Ly6C high fractions in circulating peripheral blood mononuclear cells (PBMCs), and pro-inflammatory or anti-inflammatory mediators in both bone marrow (BM) and PBMCs. Mechanistically, bulk RNA-seq and gene set enrichment analysis of ECs enriched from the aortic arch intima, as well as single cell RNA-seq from atherosclerotic lesions, revealed that endothelial miR-181a2b2 serves as a critical regulatory hub in controlling endothelial inflammation, cell adhesion, cell cycle, and immune response during atherosclerosis. Conclusions: Our study establishes that deficiency of a miRNA specifically in the vascular endothelium is sufficient to profoundly impact atherogenesis. Endothelial miR-181a2b2 deficiency regulates multiple key pathways related to endothelial inflammation, cell adhesion, cell cycle, and immune response involved in the development of atherosclerosis. Graphical abstract: Image 1 Highlights: EC-specific deletion of miR-181a2b2 accelerated atherosclerosis, cell adhesion molecule expression, and lesion macrophages. These findings were independent of body weight, lipid metabolism, or shift in the Ly6C fractions in PBMCs or bone marrow. RNA-Seq and scRNA-seq revealed pathways associated with EC inflammation, cell adhesion, cell cycle, and immune response.