Trimethylamine- N -Oxide Affects Cell Type–Specific Pathways and Networks in Mouse Aorta to Promote Atherosclerotic Plaque Vulnerability
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Le résumé fourni par la source
BACKGROUND: -oxide (TMAO) has been significantly linked to atherosclerosis via several mechanisms, but its direct effect on the atherosclerosis-prone vasculature remains unclear. The objective of this study was to characterize the cell type-dependent and independent effects of TMAO on key vascular cell types involved in atherosclerosis progression in vivo. METHODS: mice fed normal laboratory, high-cholesterol, or high-cholesterol+TMAO diets for 3 months to identify which aortic cell types, differentially expressed genes, and biological pathways are affected by TMAO. We also modeled cell-cell communications and intracellular gene regulatory networks to identify gene networks perturbed by TMAO feeding. Key genes and pathways were validated using human vascular smooth muscle cells (vSMCs) exposed to TMAO. Changes in fibrous cap thickness, macrophage content, and collagen deposition in response to TMAO were measured with immunostaining and histology and quantified. RESULTS: Our single-cell RNA-sequencing analysis revealed that TMAO supplementation upregulated apoptotic gene signatures and downregulated extracellular matrix (ECM) organization and collagen formation genes in a subset of atherosclerosis-specific modulated vSMCs. We also identified degradation of the ECM as a top pathway for vSMC-derived macrophage differentially expressed genes in response to TMAO. Network analyses supported that macrophage-vSMC communication mediates ECM remodeling. Using human smooth muscle cells exposed to TMAO in vitro, we confirmed the direct effect of TMAO on regulating collagen and apoptotic genes. In agreement with the changes in these pathways that affect plaque stability, we observed a significant decrease in fibrous cap thickness and collagen deposition in mice supplemented with TMAO. CONCLUSIONS: Our results reveal the effects of TMAO on vSMCs to promote apoptosis and decrease ECM formation and on macrophage-mediated ECM degradation to, in concert enhance atherosclerotic plaque instability.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Trimethylamine- <i>N</i> -Oxide Affects Cell Type–Specific Pathways and Networks in Mouse Aorta to Promote Atherosclerotic Plaque Vulnerability
- Date Crossref
- 01/10/2025
- Éditeur
- Ovid Technologies (Wolters Kluwer Health)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of California Department of Integrative Biology and Physiology (J.C. pays non établi dans la noticeUniversité ou école supérieure
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Cleveland Clinic pays non établi dans la noticeÉtablissement de santé
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Cleveland Clinic Lerner College of Medicine pays non établi dans la noticeÉtablissement de santé
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Center for Human Genetics pays non établi dans la noticeOrganisation à but non lucratif
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Institute of Human Genetics pays non établi dans la noticeStructure de recherche
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QB3 pays non établi dans la noticeOrganisation à but non lucratif
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Quantitative BioSciences pays non établi dans la noticeOrganisation à but non lucratif
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Department of Integrative Biology and Physiology (J.C. pays non établi dans la noticeInstitution
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Division of Cardiology pays non établi dans la noticeInstitution
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Molecular pays non établi dans la noticeInstitution
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Lerner Research Institute (Z.W. Department of Cardiovascular and Metabolic Sciences pays non établi dans la noticeStructure de recherche
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and Thoracic Institute Department of Cardiovascular Medicine pays non établi dans la noticeStructure de recherche
Department of Integrative Biology and Physiology (J.C. — University of California, Cleveland Clinic et Cleveland Clinic Lerner College of Medicine, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.