Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures

Örd, Tiit; Lönnberg, Tapio; Nurminen, Valtteri; Ravindran, Aarthi; Niskanen, Henri; Kiema, Miika; Õunap, Kadri; Maria, Maleeha; Moreau, Pierre R.; Mishra, Pashupati P.; Palani, Senthil; Virta, Jenni; Liljenbäck, Heidi; Aavik, Einari; Roivainen, Anne; Ylä‐Herttuala, Seppo; Laakkonen, Johanna P.; Lehtimäki, Terho; Kaikkonen, Minna U.

doi:10.1016/j.ajhg.2023.03.013

Cited by 16 publications

(11 citation statements)

References 75 publications

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“…To achieve an unbiased and enrichment-free analysis of ABI3 in cell types within healthy and atherosclerotic vascular walls, the ScRNA-seq data GSE205930 containing were acquired from the GEO database [ 37 ]. Following quality control and filtering cells, we applied an unbiased clustering approach to categorize cells, resulting in ten distinct subpopulations as visually depicted in the UMAP plot (Fig.…”

Section: Resultsmentioning

confidence: 99%

Unveiling the role of ABI3 and hub senescence-related genes in macrophage senescence for atherosclerotic plaque progression

Fu,

Zhang,

Liu

et al. 2023

Inflamm. Res.

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Background Atherosclerosis, characterized by abnormal arterial lipid deposition, is an age-dependent inflammatory disease and contributes to elevated morbidity and mortality. Senescent foamy macrophages are considered to be deleterious at all stages of atherosclerosis, while the underlying mechanisms remain largely unknown. In this study, we aimed to explore the senescence-related genes in macrophages diagnosis for atherosclerotic plaque progression. Methods The atherosclerosis-related datasets were retrieved from the Gene Expression Omnibus (GEO) database, and cellular senescence-associated genes were acquired from the CellAge database. R package Limma was used to screen out the differentially expressed senescence-related genes (DE-SRGs), and then three machine learning algorithms were applied to determine the hub DE-SRGs. Next, we established a nomogram model to further confirm the clinical significance of hub DE-SRGs. Finally, we validated the expression of hub SRG ABI3 by Sc-RNA seq analysis and explored the underlying mechanism of ABI3 in THP-1-derived macrophages and mouse atherosclerotic lesions. Results A total of 15 DE-SRGs were identified in macrophage-rich plaques, with five hub DE-SRGs (ABI3, CAV1, NINJ1, Nox4 and YAP1) were further screened using three machine learning algorithms. Subsequently, a nomogram predictive model confirmed the high validity of the five hub DE-SRGs for evaluating atherosclerotic plaque progression. Further, the ABI3 expression was upregulated in macrophages of advanced plaques and senescent THP-1-derived macrophages, which was consistent with the bioinformatics analysis. ABI3 knockdown abolished macrophage senescence, and the NF-κB signaling pathway contributed to ABI3-mediated macrophage senescence. Conclusion We identified five cellular senescence-associated genes for atherogenesis progression and unveiled that ABI3 might promote macrophage senescence via activation of the NF-κB pathway in atherogenesis progression, which proposes new preventive and therapeutic strategies of senolytic agents for atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

Unveiling the role of ABI3 and hub senescence-related genes in macrophage senescence for atherosclerotic plaque progression

Fu,

Zhang,

Liu

et al. 2023

Inflamm. Res.

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“…Our studies, and other recent evidence, demonstrate that endothelial cells themselves represent a key source of LRG1 in the diseased milieu ( Figure 1 ). For instance, single cell RNA sequencing revealed Lrg1 as one of the most upregulated genes in disease-associated endothelial cells in murine models of liver cancer ( 96 ) and atherosclerosis ( 97 ), while a seminal study demonstrated that LRG1 originating from endothelial cells contributes primarily, in an autocrine fashion, to vessel malfunction and disease severity in a model of emphysema ( 37 ). Interestingly, transcriptomics studies also showed higher Lrg1 expression in endothelial cells isolated from LPS-treated lungs, pointing to inflammation-induced LRG1 being responsible for aberrant vasculogenesis ( 39 ).…”

Section: Lrg1 and Angiogenesismentioning

confidence: 99%

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

Dritsoula,

Camilli,

Moss

et al. 2024

Front. Cardiovasc. Med.

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The establishment of new blood vessels, and their subsequent stabilization, is a critical process that facilitates tissue growth and organ development. Once established, vessels need to diversify to meet the specific needs of the local tissue and to maintain homeostasis. These processes are tightly regulated and fundamental to normal vessel and tissue function. The mechanisms that orchestrate angiogenesis and vessel maturation have been widely studied, with signaling crosstalk between endothelium and perivascular cells being identified as an essential component. In disease, however, new vessels develop abnormally, and existing vessels lose their specialization and function, which invariably contributes to disease progression. Despite considerable research into the vasculopathic mechanisms in disease, our knowledge remains incomplete. Accordingly, the identification of angiocrine and angiopathic molecules secreted by cells within the vascular microenvironment, and their effect on vessel behaviour, remains a major research objective. Over the last decade the secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1), has emerged as a significant vasculopathic molecule, stimulating defective angiogenesis, and destabilizing the existing vasculature mainly, but not uniquely, by altering both canonical and non-canonical TGF-β signaling in a highly cell and context dependent manner. Whilst LRG1 does not possess any overt homeostatic role in vessel development and maintenance, growing evidence provides a compelling case for LRG1 playing a pleiotropic role in disrupting the vasculature in many disease settings. Thus, LRG1 has now been reported to damage vessels in various disorders including cancer, diabetes, chronic kidney disease, ocular disease, and lung disease and the signaling processes that drive this dysfunction are being defined. Moreover, therapeutic targeting of LRG1 has been widely proposed to re-establish a quiescent endothelium and normalized vasculature. In this review, we consider the current status of our understanding of the role of LRG1 in vascular pathology, and its potential as a therapeutic target.

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“…Single-cell RNA sequencing (scRNA-seq) technology enables research at unprecedented resolution by analyzing global gene expression and regulation pathway alternation in different cell populations during disease progression. Nowadays, scRNA-seq has emerged as a powerful tool for investigating cell trajectory, RNA velocity and cell-cell communication [12,13]. ScRNA-seq has already been employed to determine cell heterogeneity in AS pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Transcriptomic Profiling Unveils Critical Metabolic Alterations and Signatures in Progression of Atherosclerosis

Ma,

Zhao,

Xiang

et al. 2024

Preprint

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Metabolic dysregulation is recognized as a fundamental characteristic of cardiovascular diseases (CVDs), therefore mining metabolic patterns in these diseases would help to identify the possible pathogenic mechanisms and potential intervention targets. Atherosclerosis (AS), serving as the foundational pathology in numerous CVDs, represents a paramount global health concern. However, a systematic integrated analysis of the metabolic networks of AS is still lacking. In this study, we investigated and integrated single-cell RNA sequencing datasets from calcified atherosclerotic core (AC) plaques and patient-matched proximal adjacent (PA) portions of carotid artery tissue to generate metabolic flux profiling at single-cell level. Using scFEA and scWGCNA analyses, we discerned common metabolic changes in endothelial cells (ECs), myeloid cells, and smooth muscle cells. These altered metabolic modules were predominantly enriched in glucose-related pathways and were predicted to potentially facilitate metabolic bypass. Of particular interest, we observed an enrichment of metabolites produced from glucose/sialic acid metabolism pathway in both ECs and myeloid cells. This observation may partially account for their positive involvement in plaque formation, as previously discovered. Furthermore, we predicted that metabolic genes such as HK1, ENO1, PFKL, LDHA, PGK1, and NANS may be implicated in the detected metabolic flux disorder during AS progression. Additionally, we uncovered interactions between various cell types at single-cell level using CellChat. We noted heightened interactions between endothelial/SMC as well as myeloid/ECs in AC group, with ITGB2/VCAM and CD44/CD74 receptors potentially participating in these interactions, thereby fostering the development of pro-inflammatory plaque microenvironment. In conclusion, our study unveils metabolic shifts at single-cell level and identifies key gene signatures associated with metabolic disorders and cell-cell communication in atherosclerosis.

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Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures

Cited by 16 publications

References 75 publications

Unveiling the role of ABI3 and hub senescence-related genes in macrophage senescence for atherosclerotic plaque progression

Unveiling the role of ABI3 and hub senescence-related genes in macrophage senescence for atherosclerotic plaque progression

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

Single-Cell Transcriptomic Profiling Unveils Critical Metabolic Alterations and Signatures in Progression of Atherosclerosis

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