Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis

While our understanding of the single-cell gene expression patterns underlying the transformation of vascular cell types during the progression of atherosclerosis is rapidly improving, the clinical and pathophysiological relevance of these changes remains poorly understood. Single-cell RNA sequencin...

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Published in:	Circulation research Vol. 134; no. 11; pp. 1405 - 1423
Main Authors:	Mocci, Giuseppe, Sukhavasi, Katyayani, Örd, Tiit, Bankier, Sean, Singha, Prosanta, Arasu, Uma Thanigai, Agbabiaje, Olayinka Oluwasegun, Mäkinen, Petri, Ma, Lijiang, Hodonsky, Chani J, Aherrahrou, Redouane, Muhl, Lars, Liu, Jianping, Gustafsson, Sonja, Byandelger, Byambajav, Wang, Ying, Koplev, Simon, Lendahl, Urban, Owens, Gary K, Leeper, Nicholas J, Pasterkamp, Gerard, Vanlandewijck, Michael, Michoel, Tom, Ruusalepp, Arno, Hao, Ke, Ylä-Herttuala, Seppo, Väli, Marika, Järve, Heli, Mokry, Michal, Civelek, Mete, Miller, Clint J, Kovacic, Jason C, Kaikkonen, Minna U, Betsholtz, Christer, Björkegren, Johan L M
Format:	Journal Article
Language:	English
Published:	United States 24-05-2024
Subjects:	Animals Atherosclerosis - genetics Atherosclerosis - metabolism Atherosclerosis - pathology coronary artery disease Disease Progression Female gene expression Gene Regulatory Networks Humans lipoportein macrophages Macrophages - metabolism Macrophages - pathology Male Medicin och hälsovetenskap Mice Mice, Inbred C57BL Mice, Knockout Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Plaque, Atherosclerotic Receptors, LDL - genetics Receptors, LDL - metabolism Single-Cell Analysis subcutaneous fat coronary artery disease macrophages lipoportein subcutaneous fat gene expression
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Summary:	While our understanding of the single-cell gene expression patterns underlying the transformation of vascular cell types during the progression of atherosclerosis is rapidly improving, the clinical and pathophysiological relevance of these changes remains poorly understood. Single-cell RNA sequencing data generated with SmartSeq2 (≈8000 genes/cell) in 16 588 single cells isolated during atherosclerosis progression in mice with human-like plasma lipoproteins and from humans with asymptomatic and symptomatic carotid plaques was clustered into multiple subtypes. For clinical and pathophysiological context, the advanced-stage and symptomatic subtype clusters were integrated with 135 tissue-specific (atherosclerotic aortic wall, mammary artery, liver, skeletal muscle, and visceral and subcutaneous, fat) gene-regulatory networks (GRNs) inferred from 600 coronary artery disease patients in the STARNET (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task) study. Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated (macrophage) phenotypes. Integrative analysis of these 6 clusters with STARNET revealed significant enrichments of 3 arterial wall GRNs: GRN33 (macrophage), GRN39 (SMC), and GRN122 (macrophage) with major contributions to coronary artery disease heritability and strong associations with clinical scores of coronary atherosclerosis severity. The presence and pathophysiological relevance of GRN39 were verified in 5 independent RNAseq data sets obtained from the human coronary and aortic artery, and primary SMCs and by targeting its top-key drivers, and in cultured human coronary artery SMCs. By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced, symptomatic atherosclerosis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-7330 1524-4571 1524-4571
DOI:	10.1161/CIRCRESAHA.123.323184