Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis-Reference-Cited by-同舟云学术

Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis

Published:2024-05-24 Issue:11 Volume:134 Page:1405-1423
ISSN:0009-7330
Container-title:Circulation Research
language:en
Short-container-title:Circulation Research

Author:

Mocci Giuseppe¹,Sukhavasi Katyayani²^ORCID,Örd Tiit³,Bankier Sean⁴^ORCID,Singha Prosanta³^ORCID,Arasu Uma Thanigai³^ORCID,Agbabiaje Olayinka Oluwasegun³,Mäkinen Petri³^ORCID,Ma Lijiang⁵,Hodonsky Chani J.⁶⁷,Aherrahrou Redouane⁷⁸^ORCID,Muhl Lars¹,Liu Jianping¹^ORCID,Gustafsson Sonja¹^ORCID,Byandelger Byambajav¹^ORCID,Wang Ying⁹¹⁰^ORCID,Koplev Simon⁵¹¹,Lendahl Urban¹^ORCID,Owens Gary K.⁶^ORCID,Leeper Nicholas J.⁹¹⁰^ORCID,Pasterkamp Gerard¹²¹³^ORCID,Vanlandewijck Michael¹^ORCID,Michoel Tom⁴^ORCID,Ruusalepp Arno²^ORCID,Hao Ke⁵,Ylä-Herttuala Seppo³^ORCID,Väli Marika¹⁴¹⁵,Järve Heli²,Mokry Michal³¹²^ORCID,Civelek Mete⁷⁸^ORCID,Miller Clint J.⁶^ORCID,Kovacic Jason C.¹⁶¹⁷¹⁸^ORCID,Kaikkonen Minna U.³^ORCID,Betsholtz Christer¹¹⁴^ORCID,Björkegren Johan L.M.¹⁵¹⁹

Affiliation:

1. Department of Medicine (Huddinge), Karolinska Institutet, Sweden (G.M., L. Muhl, J.L., S.G., B.B., U.L., M.V., C.B., J.L.M.B.).

2. Department of Cardiac Surgery and The Heart Clinic, Tartu University Hospital and Department of Cardiology, Institute of Clinical Medicine, Tartu University, Estonia (K.S., A.R., H.J.).

3. A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio (T.O., P.S., U.T.A., O.O.A., P.M., S.Y.-H., M.U.K.).

4. Computational Biology Unit, Department of Informatics, University of Bergen, Norway (S.B., T.M.).

5. Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York (L. Ma, S.K., K.H., J.L.M.B.).

6. Robert M. Berne Cardiovascular Research Center (C.J.H., G.K.O., C.J.M.), University of Virginia, Charlottesville.

7. Center for Public Health Genomics (C.J.H., R.A., M.C.), University of Virginia, Charlottesville.

8. Department of Biomedical Engineering (R.A., M.C.), University of Virginia, Charlottesville.

9. Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, CA (Y.W., N.J.L.).

10. Stanford Cardiovascular Institute, Stanford University, CA (Y.W., N.J.L.).

11. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, United Kingdom (S.K.).

12. Laboratory of Experimental Cardiology (G.P., M.M.), University Medical Center Utrecht, the Netherlands.

13. Central Diagnostics Laboratory (G.P., M.M.), University Medical Center Utrecht, the Netherlands.

14. Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Sweden (M.V., C.B.).

15. Department of Pathological anatomy and Forensic medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia (M.V.).

16. Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York (J.C.K.).

17. Victor Chang Cardiac Research Institute, Darlinghurst, Australia (J.C.K.).

18. St. Vincent’s Clinical School, University of NSW, Sydney, Australia (J.C.K.).

19. Clinical Gene Networks AB, Stockholm, Sweden (J.L.M.B.).

Abstract

BACKGROUND: 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. METHODS: Single-cell RNA sequencing data generated with SmartSeq2 (≈8000 genes/cell) in 16 588 single cells isolated during atherosclerosis progression in Ldlr −/− Apob 100/100 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. RESULTS: 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, FRZB and ALCAM in cultured human coronary artery SMCs. CONCLUSIONS: 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Reference65 articles.

1. Atherosclerosis: Recent developments

2. Single-Cell RNA-Seq Reveals a Crosstalk between Hyaluronan Receptor LYVE-1-Expressing Macrophages and Vascular Smooth Muscle Cells

3. Stem Cell Pluripotency Genes Klf4 and Oct4 Regulate Complex SMC Phenotypic Changes Critical in Late-Stage Atherosclerotic Lesion Pathogenesis

4. Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas

5. Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human

Cited by 1 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. RNA Sequencing Atherosclerosis Data Sets: Expanding Potential Therapeutic Targets;Circulation Research;2024-05-24