Integrated single-cell RNA-seq analysis reveals the vital cell types and dynamic development signature of atherosclerosis

Introduction: In the development of atherosclerosis, the remodeling of blood vessels is a key process involving plaque formation and rupture. So far, most reports mainly believe that macrophages, smooth muscle cells, and endothelial cells located at the intima and media of artery play the key role in this process. Few studies had focused on whether fibroblasts located at adventitia are involved in regulating disease process. Methods and results: In this study, we conducted in-depth analysis of single-cell RNA-seq data of the total of 18 samples from healthy and atherosclerotic arteries. This study combines several analysis methods including transcription regulator network, cell-cell communication network, pseudotime trajectory, gene set enrichment analysis, and differential expression analysis. We found that SERPINF1 is highly expressed in fibroblasts and is involved in the regulation of various signaling pathways. Conclusion: Our research reveals a potential mechanism of atherosclerosis, SERPINF1 regulates the formation and rupture of plaques through the Jak-STAT signaling pathway, which may provide new insights into the pathological study of disease. Moreover, we suggest that SRGN and IGKC as potential biomarkers for unstable arterial plaques.

[1]  Douglas B. Cowan,et al.  Targeting Epsins to Inhibit Fibroblast Growth Factor Signaling While Potentiating Transforming Growth Factor-β Signaling Constrains Endothelial-to-Mesenchymal Transition in Atherosclerosis , 2023, Circulation.

[2]  Douglas B. Cowan,et al.  Epsin Nanotherapy Regulates Cholesterol Transport to Fortify Atheroma Regression , 2022, Circulation research.

[3]  Mingyao Li,et al.  Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human , 2020, Circulation.

[4]  G. Paulsson-Berne,et al.  Treatment with a Toll‐like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice , 2020, Journal of internal medicine.

[5]  Xinran Liu,et al.  Cav-1 (Caveolin-1) Deficiency Increases Autophagy in the Endothelium and Attenuates Vascular Inflammation and Atherosclerosis , 2020, Arteriosclerosis, thrombosis, and vascular biology.

[6]  Jie Xiao,et al.  Experimental abdominal aortic aneurysm growth is inhibited by blocking the JAK2/STAT3 pathway. , 2020, International journal of cardiology.

[7]  Ruth R. Montgomery,et al.  Smooth Muscle Cell Reprogramming in Aortic Aneurysms. , 2020, Cell stem cell.

[8]  Z. Yue,et al.  The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis , 2020, Autophagy.

[9]  Mirjana Efremova,et al.  CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes , 2020, Nature Protocols.

[10]  A. Tall,et al.  Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe−/− Mice , 2020, Cardiovascular Drugs and Therapy.

[11]  西川 真生,et al.  Pigment Epithelium-Derived Factor , 2020, Definitions.

[12]  H. Daida,et al.  JAK-STAT-dependent regulation of scavenger receptors in LPS-activated murine macrophages. , 2020, European journal of pharmacology.

[13]  Hui Li,et al.  Pigment Epithelial‐Derived Factor Deficiency Accelerates Atherosclerosis Development via Promoting Endothelial Fatty Acid Uptake in Mice With Hyperlipidemia , 2019, Journal of the American Heart Association.

[14]  Zheng Duanmu,et al.  Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit , 2019, BMC Cardiovascular Disorders.

[15]  P. Libby,et al.  Atherosclerosis , 2019, Nature Reviews Disease Primers.

[16]  I. Ulitsky,et al.  The Human-Specific and Smooth Muscle Cell-Enriched LncRNA SMILR Promotes Proliferation by Regulating Mitotic CENPF mRNA and Drives Cell-Cycle Progression Which Can Be Targeted to Limit Vascular Remodeling , 2019, Circulation research.

[17]  A. D'Ascola,et al.  Serglycin as part of IL-1β induced inflammation in human chondrocytes. , 2019, Archives of biochemistry and biophysics.

[18]  Clint L. Miller,et al.  Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis , 2019, Nature Medicine.

[19]  Olga Tanaseichuk,et al.  Metascape provides a biologist-oriented resource for the analysis of systems-level datasets , 2019, Nature Communications.

[20]  Ying Wang,et al.  A functional variant of SMAD4 enhances macrophage recruitment and inflammatory response via TGF-β signal activation in Thoracic aortic aneurysm and dissection , 2018, Aging.

[21]  Shuxia Wang,et al.  The effects of pigment epithelium-derived factor on atherosclerosis: putative mechanisms of the process , 2018, Lipids in Health and Disease.

[22]  Chunxiang Zhang,et al.  Activation of NLRP3 Inflammasome Promotes Foam Cell Formation in Vascular Smooth Muscle Cells and Atherogenesis Via HMGB1 , 2018, Journal of the American Heart Association.

[23]  K. Moore,et al.  Regulation of macrophage immunometabolism in atherosclerosis , 2018, Nature Immunology.

[24]  G. Hansson,et al.  Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells—Brief Report , 2018, Arteriosclerosis, thrombosis, and vascular biology.

[25]  Paul Hoffman,et al.  Integrating single-cell transcriptomic data across different conditions, technologies, and species , 2018, Nature Biotechnology.

[26]  Guixue Wang,et al.  A Novel Role of Id1 in Regulating Oscillatory Shear Stress-Mediated Lipid Uptake in Endothelial Cells , 2018, Annals of Biomedical Engineering.

[27]  P. Emery,et al.  Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor , 2017, Annals of the rheumatic diseases.

[28]  Hannah A. Pliner,et al.  Reversed graph embedding resolves complex single-cell trajectories , 2017, Nature Methods.

[29]  J. Aerts,et al.  SCENIC: Single-cell regulatory network inference and clustering , 2017, Nature Methods.

[30]  Huixia Lu,et al.  PEDF improves atherosclerotic plaque stability by inhibiting macrophage inflammation response. , 2017, International journal of cardiology.

[31]  Jian-xing Ma,et al.  Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway. , 2017, Kidney international.

[32]  Weston R. Spivia,et al.  Macrophage molecular signaling and inflammatory responses during ingestion of atherogenic lipoproteins are modulated by complement protein C1q. , 2016, Atherosclerosis.

[33]  V. Fuster,et al.  Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability , 2016, Nature Communications.

[34]  P. Delafontaine,et al.  Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E–Deficient Mice , 2016, Circulation.

[35]  G. Garcı́a-Cardeña,et al.  Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. , 2016, Circulation research.

[36]  W. Min,et al.  SOCS1 prevents graft arteriosclerosis by preserving endothelial cell function. , 2014, Journal of the American College of Cardiology.

[37]  Hongmin Chen,et al.  Pigment epithelium-derived factor inhibits high glucose-induced JAK/STAT signalling pathway activation in human glomerular mesangial cells. , 2013, Saudi medical journal.

[38]  P. Libby,et al.  Local proliferation dominates lesional macrophage accumulation in atherosclerosis , 2013, Nature Medicine.

[39]  S. Della Bella,et al.  Engagement of NKp30 on Vδ1 T cells induces the production of CCL3, CCL4, and CCL5 and suppresses HIV-1 replication. , 2012, Blood.

[40]  T. Imaizumi,et al.  Serum level of pigment epithelium-derived factor is a marker of atherosclerosis in humans. , 2011, Atherosclerosis.

[41]  P. Libby,et al.  Progress and challenges in translating the biology of atherosclerosis , 2011, Nature.

[42]  A. Swain,et al.  Wnt4/&bgr;-Catenin Signaling Induces VSMC Proliferation and Is Associated With Intimal Thickening , 2011, Circulation research.

[43]  S. Nees,et al.  Pericytes in the macrovascular intima: possible physiological and pathogenetic impact. , 2010, American journal of physiology. Heart and circulatory physiology.

[44]  D. Dichek,et al.  TGF-&bgr;1 Limits Plaque Growth, Stabilizes Plaque Structure, and Prevents Aortic Dilation in Apolipoprotein E–Null Mice , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[45]  A. Ortiz,et al.  Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells. , 2009, Cardiovascular research.

[46]  J. Egido,et al.  Suppressors of Cytokine Signaling Modulate JAK/STAT-Mediated Cell Responses During Atherosclerosis , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[47]  C. Stefanadis,et al.  Atherosclerosis of the aorta in patients with acute thoracic aortic dissection. , 2008, Circulation journal : official journal of the Japanese Circulation Society.

[48]  P. Carmeliet,et al.  Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis , 2008, The Journal of pathology.

[49]  R. Virmani,et al.  Signal Transducer and Activator of Transcription-1 Is Critical for Apoptosis in Macrophages Subjected to Endoplasmic Reticulum Stress In Vitro and in Advanced Atherosclerotic Lesions In Vivo , 2008, Circulation.

[50]  Jill P. Mesirov,et al.  GSEA-P: a desktop application for Gene Set Enrichment Analysis , 2007, Bioinform..

[51]  A. Al Haj Zen,et al.  Decorin overexpression reduces atherosclerosis development in apolipoprotein E-deficient mice. , 2006, Atherosclerosis.

[52]  D. Harrison,et al.  The JAK/STAT signaling pathway , 2004, Journal of Cell Science.

[53]  Y. Sugisaki,et al.  Expression of lumican in thickened intima and smooth muscle cells in human coronary atherosclerosis. , 2002, Experimental and molecular pathology.

[54]  A. Chiavegato,et al.  Contribution of Adventitial Fibroblasts to Neointima Formation and Vascular Remodeling: From Innocent Bystander to Active Participant , 2001, Circulation research.

[55]  A. Zalewski,et al.  Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. , 1996, Circulation.

[56]  in in Humans. , 2021 .

[57]  Xiaolu Yang,et al.  Inhibition of JAK2/STAT3-mediated VEGF upregulation under high glucose conditions by PEDF through a mitochondrial ROS pathway in vitro. , 2010, Investigative ophthalmology & visual science.

[58]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[59]  J. Kinet,et al.  The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. , 1999 .

[60]  R. Ross,et al.  ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.