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

Circulation ◽  
2020 ◽  
Vol 142 (21) ◽  
pp. 2060-2075 ◽  
Author(s):  
Huize Pan ◽  
Chenyi Xue ◽  
Benjamin J. Auerbach ◽  
Jiaxin Fan ◽  
Alexander C. Bashore ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Single Cell ◽  
Phenotypic Switching ◽  
Atherosclerotic Plaques ◽  
Fate Mapping ◽  
Human Genomics ◽  
Single Cell Genomics ◽  
Artery Disease

Background: Smooth muscle cells (SMCs) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration, and transdifferentiation into other cell types. Yet how SMCs contribute to the pathophysiology of atherosclerosis remains elusive. Methods: To reveal the trajectories of SMC transdifferentiation during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of both mouse and human atherosclerotic plaques. We also performed cell biology experiments on isolated SMC-derived cells, conducted integrative human genomics, and used pharmacological studies targeting SMC-derived cells both in vivo and in vitro. Results: We found that SMCs transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. SMC-derived intermediate cells, termed “SEM” cells (stem cell, endothelial cell, monocyte), were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return toward the SMC phenotype. Retinoic acid (RA) signaling was identified as a regulator of SMC to SEM cell transition, and RA signaling was dysregulated in symptomatic human atherosclerosis. Human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene loci and correlation between coronary artery disease risk alleles and repressed expression of these genes. Activation of RA signaling by all-trans RA, an anticancer drug for acute promyelocytic leukemia, blocked SMC transition to SEM cells, reduced atherosclerotic burden, and promoted fibrous cap stability. Conclusions: Integration of cell-specific fate mapping, single-cell genomics, and human genetics adds novel insights into the complexity of SMC biology and reveals regulatory pathways for therapeutic targeting of SMC transitions in atherosclerotic cardiovascular disease.

scholarly journals Intersecting single-cell transcriptomics and genome-wide association studies identifies crucial cell populations and candidate genes for atherosclerosis

2021 ◽  
Author(s):  
Lotte Slenders ◽  
Lennart P L Landsmeer ◽  
Kai Cui ◽  
Marie A C Depuydt ◽  
Maarten Verwer ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Smooth Muscle ◽  
Single Cell ◽  
Candidate Genes ◽  
Atherosclerotic Disease ◽  
Cell Populations ◽  
Atherosclerotic Plaques ◽  
Biological Mechanisms ◽  
Artery Disease

Abstract Aim GWASs have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into biological mechanisms and targets for drug discovery remains challenging. Intersecting genetic and gene expression data has led to the identification of candidate genes. However, previously studied tissues are often non-diseased and heterogeneous in cell composition, hindering accurate candidate prioritization. Therefore, we analyzed single-cell transcriptomics from atherosclerotic plaques for cell-type-specific expression to identify atherosclerosis-associated candidate gene-cell pairs. Methods and Results We applied gene-based analyses using GWAS summary statistics from 46 atherosclerotic and cardiovascular disease, risk factors, and other traits. We then intersected these candidates with scRNA-seq data to identify genes specific for individual cell (sub)populations in atherosclerotic plaques. The coronary artery disease loci demonstrated a prominent signal in plaque smooth muscle cells (SKI, KANK2, SORT1) p-adj. = 0.0012, and endothelial cells (SLC44A1, ATP2B1) p-adj. = 0.0011. Finally, we used liver-derived scRNA-seq data and showed hepatocyte-specific enrichment of genes involved in serum lipid levels. Conclusion We discovered novel and known gene-cell pairs pointing to new biological mechanisms of atherosclerotic disease. We highlight that loci associated with coronary artery disease reveal prominent association levels in mainly plaque smooth muscle cell and endothelial cell populations. We present an intuitive single-cell transcriptomics-driven workflow rooted in human large-scale genetic studies to identify putative candidate genes and affected cells associated with cardiovascular traits. Collectively, our workflow allows for the identification of cell-specific targets relevant for atherosclerosis and can be universally applied to other complex genetic diseases and traits. Translational perspective GWAS identified a large number of genomic loci associated with atherosclerotic disease. The translation of these results into drug development and faster diagnostics remains challenging. With our approach, we cross-reference the GWAS findings for atherosclerotic disease with scRNA-seq data of disease-relevant tissue and bring the GWAS findings closer to the functional and mechanistic studies.

scholarly journals TGFβ, smooth muscle cells and coronary artery disease: a review

2019 ◽  
Vol 53 ◽  
pp. 90-101 ◽  
Author(s):  
Emma L. Low ◽  
Andrew H. Baker ◽  
Angela C. Bradshaw
Keyword(s):  
Coronary Artery Disease ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Artery Disease

scholarly journals High Plasma Levels of Soluble Talin-1 in Patients with Coronary Artery Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Masayuki Aoyama ◽  
Yoshimi Kishimoto ◽  
Emi Saita ◽  
Yukinori Ikegami ◽  
Reiko Ohmori ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Coronary Vessels ◽  
Focal Adhesions ◽  
High Plasma ◽  
Blood Levels ◽  
Atherosclerotic Plaques ◽  
Vessel Disease ◽  
Artery Disease

Aims. Talin-1 is a cytoskeletal protein that binds integrin, thereby leading to integrin activation and affecting focal adhesions. Recently, talin-1 expression was reported to be downregulated in human atherosclerotic plaques. However, blood levels of soluble talin-1 (sTalin-1) in patients with atherosclerotic disease, such as coronary artery disease (CAD), have not been elucidated. Methods. We measured plasma sTalin-1 levels in 349 patients undergoing elective coronary angiography. The severity of CAD was represented as the number of stenotic coronary vessels and segments. Results. Of the 349 study patients, CAD was found in 194 patients, of whom 88 had 1-vessel disease (1-VD), 60 had 2-vessel disease (2-VD), and 46 had 3-vessel disease (3-VD). Plasma sTalin-1 levels were higher in 194 patients with CAD than in 155 without CAD (CAD(-) group) (median 0.30 vs. 0.23 ng/mL, P<0.005). A stepwise increase in sTalin-1 levels was found depending on the number of >50% stenotic coronary vessels: 0.23 in CAD(-), 0.29 in 1-VD, 0.30 in 2-VD, and 0.32 ng/mL in 3-VD group, respectively, (P<0.05). High sTalin-1 level (>0.28 ng/mL) was found in 36% of CAD(-), 51% of 1-VD, 53% of 2-VD, and 59% of 3-VD group (P<0.025). sTalin-1 levels also correlated with the number of >50% stenotic segments (r=0.14, P<0.02). The multivariate analysis revealed that sTalin-1 levels were independently associated with CAD. The odds ratio for CAD was 1.83 (95%CI=1.14−2.93) for high sTalin-1 level (>0.28 ng/mL) (P<0.02). Conclusions. Plasma sTalin-1 levels in patients with CAD were found to be high and to be associated with the presence and severity of CAD, suggesting a role of sTalin-1 in the progression of coronary atherosclerosis.

scholarly journals Single‐Cell Immune Profiling in Coronary Artery Disease: The Role of State‐of‐the‐Art Immunophenotyping With Mass Cytometry in the Diagnosis of Atherosclerosis

2020 ◽  
Vol 9 (24) ◽  
Author(s):  
Katharine A. Kott ◽  
Stephen T. Vernon ◽  
Thomas Hansen ◽  
Macha de Dreu ◽  
Souvik K. Das ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Single Cell ◽  
Immune Cell ◽  
Mass Cytometry ◽  
Artery Disease ◽  
Immune Cell Subpopulations ◽  
Cell Subpopulations ◽  
Serological Biomarkers

Abstract Coronary artery disease remains the leading cause of death globally and is a major burden to every health system in the world. There have been significant improvements in risk modification, treatments, and mortality; however, our ability to detect asymptomatic disease for early intervention remains limited. Recent discoveries regarding the inflammatory nature of atherosclerosis have prompted investigation into new methods of diagnosis and treatment of coronary artery disease. This article reviews some of the highlights of the important developments in cardioimmunology and summarizes the clinical evidence linking the immune system and atherosclerosis. It provides an overview of the major serological biomarkers that have been associated with atherosclerosis, noting the limitations of these markers attributable to low specificity, and then contrasts these serological markers with the circulating immune cell subtypes that have been found to be altered in coronary artery disease. This review then outlines the technique of mass cytometry and its ability to provide high‐dimensional single‐cell data and explores how this high‐resolution quantification of specific immune cell subpopulations may assist in the diagnosis of early atherosclerosis in combination with other complimentary techniques such as single‐cell RNA sequencing. We propose that this improved specificity has the potential to transform the detection of coronary artery disease in its early phases, facilitating targeted preventative approaches in the precision medicine era.

Coronary artery disease

2012 ◽  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Antihypertensive Drugs ◽  
Lipid Lowering ◽  
Atherosclerotic Plaques ◽  
Lipid Lowering Therapy ◽  
Lipid Management ◽  
Lowering Therapy ◽  
Artery Disease

Atherosclerosis: pathophysiology 212Development of atherosclerotic plaques 214Epidemiology 216Assessment of atherosclerotic risk 218Risk factors for coronary artery disease 220Hypertension 226Treatment of high blood pressure 228Combining antihypertensive drugs 230Lipid management in atherosclerosis 232Lipid-lowering therapy 236When to treat lipids ...

Coronary artery disease and activation of the atherosclerotic plaques

1992 ◽  
Vol 65 ◽  
pp. S10
Author(s):  
E. Arbustini ◽  
M. Grasso ◽  
M. Diegoli ◽  
M. Bramerio ◽  
A. Aguzzi ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Atherosclerotic Plaques ◽  
Artery Disease

Helicobacter species in the atherosclerotic plaques of patients with coronary artery disease

2012 ◽  
Vol 21 (4) ◽  
pp. 307-311 ◽  
Author(s):  
Morteza Izadi ◽  
Mojgan Fazel ◽  
Seyed Hossein Sharubandi ◽  
Seyed Hassan Saadat ◽  
Maryam Moshkani Farahani ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Atherosclerotic Plaques ◽  
Artery Disease
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