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Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis.
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.
Afiliação
  • Mocci G; 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.).
  • Sukhavasi K; 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.).
  • Örd T; 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.).
  • Bankier S; Computational Biology Unit, Department of Informatics, University of Bergen, Norway (S.B., T.M.).
  • Singha P; 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.).
  • Arasu UT; 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.).
  • Agbabiaje OO; 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.).
  • Mäkinen P; 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.).
  • Ma L; 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.).
  • Hodonsky CJ; Robert M. Berne Cardiovascular Research Center (C.J.H., G.K.O., C.J.M.), University of Virginia, Charlottesville.
  • Aherrahrou R; Center for Public Health Genomics (C.J.H., R.A., M.C.), University of Virginia, Charlottesville.
  • Muhl L; Center for Public Health Genomics (C.J.H., R.A., M.C.), University of Virginia, Charlottesville.
  • Liu J; Department of Biomedical Engineering (R.A., M.C.), University of Virginia, Charlottesville.
  • Gustafsson S; 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.).
  • Byandelger B; 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.).
  • Wang Y; 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.).
  • Koplev S; 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.).
  • Lendahl U; Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, CA (Y.W., N.J.L.).
  • Owens GK; Stanford Cardiovascular Institute, Stanford University, CA (Y.W., N.J.L.).
  • Leeper NJ; 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.).
  • Pasterkamp G; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, United Kingdom (S.K.).
  • Vanlandewijck M; 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.).
  • Michoel T; Robert M. Berne Cardiovascular Research Center (C.J.H., G.K.O., C.J.M.), University of Virginia, Charlottesville.
  • Ruusalepp A; Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, CA (Y.W., N.J.L.).
  • Hao K; Stanford Cardiovascular Institute, Stanford University, CA (Y.W., N.J.L.).
  • Ylä-Herttuala S; Laboratory of Experimental Cardiology (G.P., M.M.), University Medical Center Utrecht, the Netherlands.
  • Väli M; Central Diagnostics Laboratory (G.P., M.M.), University Medical Center Utrecht, the Netherlands.
  • Järve H; 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.).
  • Mokry M; Computational Biology Unit, Department of Informatics, University of Bergen, Norway (S.B., T.M.).
  • Civelek M; 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.).
  • Miller CJ; 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.).
  • Kovacic JC; 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.).
  • Kaikkonen MU; Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Sweden (M.V., C.B.).
  • Betsholtz C; Department of Pathological anatomy and Forensic medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia (M.V.).
  • Björkegren JLM; 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.).
Circ Res ; 134(11): 1405-1423, 2024 May 24.
Article em En | MEDLINE | ID: mdl-38639096
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-/-Apob100/100 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aterosclerose / Redes Reguladoras de Genes / Análise de Célula Única Limite: Animals / Female / Humans / Male Idioma: En Revista: Circ Res Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Aterosclerose / Redes Reguladoras de Genes / Análise de Célula Única Limite: Animals / Female / Humans / Male Idioma: En Revista: Circ Res Ano de publicação: 2024 Tipo de documento: Article