Integrative multiomics analysis of human atherosclerosis reveals a serum response factor‐driven network associated with intraplaque hemorrhage

Jin, Han; Goossens, Pieter; Juhász, Péter; Eijgelaar, Wouter J.; Manca, Marco; Karel, Joël; Smirnov, Evgueni; Sikkink, C.J.J.M.; Mees, Barend; Waring, Olivia J.; Kuijk, Kim van; Fazzi, Gregorio E.; Gijbels, Marion J.J.; Kutmon, Martina; Evelo, Chris T.; Hedin, Ulf; Daemen, M. J. A. P.; Sluimer, Judith C.; Matic, Ljubica; Biessen, Erik A. L.

doi:10.1002/ctm2.458

Cited by 37 publications

(22 citation statements)

References 59 publications

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“…Similarly, LAMP -2A messenger RNA (mRNA) levels in carotid plaques, surgically retrieved from symptomatic patients (from ref. 43 ; see details in SI Appendix , Methods , study 2), directly correlated with the size of the plaque but not the necrotic core ( Fig. 5 E and F ).…”

Section: Resultsmentioning

confidence: 90%

Protective role of chaperone-mediated autophagy against atherosclerosis

Madrigal‐Matute

Bruijn

Kuijk

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Cardiovascular diseases remain the leading cause of death worldwide, with atherosclerosis being the most common source of clinical events. Metabolic changes with aging associate with concurrent increased risk of both type 2 diabetes and cardiovascular disease, with the former further raising the risk of the latter. The activity of a selective type of autophagy, chaperone-mediated autophagy (CMA), decreases with age or upon dietary excesses. Here we study whether reduced CMA activity increases risk of atherosclerosis in mouse models. We have identified that CMA is up-regulated early in response to proatherogenic challenges and demonstrate that reduced systemic CMA aggravates vascular pathology in these conditions. We also provide proof-of-concept support that CMA up-regulation is an effective intervention to reduce atherosclerosis severity and progression.

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Section: Resultsmentioning

confidence: 90%

Protective role of chaperone-mediated autophagy against atherosclerosis

Madrigal‐Matute

Bruijn

Kuijk

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Our data suggests that macrophages are dysregulated in atherosclerotic plaque tissues, and that they participate in the inflammatory progression of atherosclerosis by accumulating their fraction. One protein-gene-associated multi-omics model between low- and high-risk lesion segments revealed that it was corrected with Arg1 + macrophage content and αSMA − PDGFRα + fibroblast-like cell content [ 49 ]. We also found that M2 macrophage (Arg1 + ) showed a higher fraction in plaque (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…3 A), but fibroblast-like cells were not fully identified. Gene set over-representation analysis pointed to a clear cardiovascular disease signature, including extracellular matrix synthesis and organization, and focal adhesion [ 49 ], which were also observed in enriched pathways of DEGs. Meanwhile, T follicular helper (Tfh) cells were also specifically enriched in plaque samples.…”

Section: Discussionmentioning

confidence: 99%

Integrated investigation of DNA methylation, gene expression and immune cell population revealed immune cell infiltration associated with atherosclerotic plaque formation

Yin

Xie

Chen³

et al. 2022

BMC Med Genomics

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Background The clinical consequences of atherosclerosis are significant source of morbidity and mortality throughout the world, while the molecular mechanisms of the pathogenesis of atherosclerosis are largely unknown. Methods In this study, we integrated the DNA methylation and gene expression data in atherosclerotic plaque samples to decipher the underlying association between epigenetic and transcriptional regulation. Immune cell classification was performed on the basis of the expression pattern of detected genes. Finally, we selected ten genes with dysregulated methylation and expression levels for RT-qPCR validation. Results Global DNA methylation profile showed obvious changes between normal aortic and atherosclerotic lesion tissues. We found that differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were highly associated with atherosclerosis by being enriched in atherosclerotic plaque formation-related pathways, including cell adhesion and extracellular matrix organization. Immune cell fraction analysis revealed that a large number of immune cells, especially macrophages, activated mast cells, NK cells, and Tfh cells, were specifically enriched in the plaque. DEGs associated with immune cell fraction change showed that they were mainly related to the level of macrophages, monocytes, resting NK cells, activated CD4 memory T cells, and gamma delta T cells. These genes were highly enriched in multiple pathways of atherosclerotic plaque formation, including blood vessel remodeling, collagen fiber organization, cell adhesion, collagen catalogic process, extractable matrix assembly, and platelet activation. We also validated the expression alteration of ten genes associated with infiltrating immune cells in atherosclerosis. Conclusions In conclusion, these findings provide new evidence for understanding the mechanisms of atherosclerotic plaque formation, and provide a new and valuable research direction based on immune cell infiltration.

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“…In addition, the GSE163154 dataset consists of 43 pathologically detected absent ( N = 16) or present ( N = 27) intraplaque hemorrhages in carotid plaques. The expression profile arrays of GSE163154 were generated using the GPL6104 platform [ 23 ]. Figure 1 shows the flowchart of this study.…”

Section: Methodsmentioning

confidence: 99%

Pyroptosis-Related Gene Signature and Expression Patterns in the Deterioration of Atherosclerosis

Ma²,

Wang

et al. 2022

Disease Markers

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Background. Pyroptosis has been shown to be involved in the overall process of atherosclerosis. This study was aimed at investigating pyroptosis-related gene expression patterns in atherosclerosis and their diagnostic significance. Methods and Results. In GSE100927, fifty-four pyroptosis-related genes were identified. Between atherosclerotic plaques and normal samples, the expression patterns of pyroptosis-related genes were significantly different. In order to construct a pyroptosis-related risk score signature (PRSS), the least absolute shrinkage and selection operator (LASSO) was combined with multivariate logistic regression to screen twelve genes. The diagnostic efficiency of the PRSS performed well in GSE43292, as shown by the results of receiver-operating characteristics (ROCs). Consensus clustering identified two expression patterns of pyroptosis-related genes in different statuses of atherosclerotic plaque in GSE163154. The biological behavior of the different clusters was examined by the gene set variation analysis (GSVA). The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses revealed that the differentially expressed genes (DEGs) in the two clusters were enriched in the immune response. The Cytoscape software was used to construct protein-protein interaction (PPI) networks for hub gene screening. Following that, the Drug Gene Interaction Database (DGIdb) was utilized to find 47 possible medicines and chemical compounds that interact with hub genes in atherosclerotic plaques. Conclusion. The results of this study showed that pyroptosis-related genes contribute to the progression of atherosclerosis and may serve as biomarkers in clinical diagnosis as well as novel therapeutic targets for the treatment of AS.

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Integrative multiomics analysis of human atherosclerosis reveals a serum response factor‐driven network associated with intraplaque hemorrhage

Cited by 37 publications

References 59 publications

Protective role of chaperone-mediated autophagy against atherosclerosis

Protective role of chaperone-mediated autophagy against atherosclerosis

Integrated investigation of DNA methylation, gene expression and immune cell population revealed immune cell infiltration associated with atherosclerotic plaque formation

Pyroptosis-Related Gene Signature and Expression Patterns in the Deterioration of Atherosclerosis

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