Endothelial cell-specific deletion of a microRNA accelerates atherosclerosis

Authors

Dafeng Yang, Brigham and Women’s Hospital, Harvard Medical School
Stefan Haemmig, Brigham and Women’s Hospital, Harvard Medical School
Jingshu Chen, Brigham and Women’s Hospital, Harvard Medical School
Michael McCoy, Brigham and Women’s Hospital, Harvard Medical School
Henry S. Cheng, Brigham and Women’s Hospital, Harvard Medical School
Haoyang Zhou, The Second Xiangya Hospital of Central South University, Changsha
Daniel Pérez-Cremades, Brigham and Women’s Hospital, Harvard Medical School
Xiao Cheng, University of Nebraska–LincolnFollow
Xinghui Sun, University of Nebraska - LincolnFollow
Jorge Haneo-Mejia, University of Pennsylvania
Shamsudheen K. Vellarikkal, Brigham and Women’s Hospital, Harvard Medical School
Rajat M. Gupta, Brigham and Women’s Hospital, Harvard Medical School
Victor Barrera, Harvard T.H. Chan School of Public Health
Mark W. Feinberg, Brigham and Women’s Hospital, Harvard Medical School

Date of this Version

2022

Citation

Published in final edited form as: Atherosclerosis. 2022 June ; 350: 9–18. doi:10.1016/j.atherosclerosis.2022.04.010.

HHS Public Access Author manuscript Atherosclerosis. Author manuscript; available in PMC 2023 May 08.

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.