ArticlePLoS genetics2018
Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 3 of them syntheses that pooled it.
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Who cites it
39 citing papers in PubMed, 3 syntheses or guidelines pooled it, 61 citations in OpenAlex.
- Advances in the study of exosomes in cardiovascular diseases.Journal of advanced research · 2024Pooled it
- Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis.Cell reports · 2023Pooled it
- Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease.Nature genetics · 2020Pooled it
- Patient induced pluripotent stem cells identify specificities of a reticular pseudodrusen phenotype in age-related macular degeneration.Genome medicine · 2026Article
- Genome-wide association study of frailty and integrative functional analysis to elucidate its relationship with aging.GeroScience · 2026Article
- Risk of Cardiovascular Disease Mortality in Patients With Diagnosed Cancer and Associated Genetic and Proteomic Mechanisms: A UK Biobank-Based Cohort Study.Journal of the American Heart Association · 2026Article
- Review
- Epigenomic landscape of single vascular cells reflects developmental origin and disease risk loci.Molecular systems biology · 2025Article
- Tcf21 modulates fibroblast activation and promotes cardiac fibrosis after injury via Pdgfrb signaling.Scientific reports · 2025Article
- The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci.bioRxiv : the preprint server for biology · 2025Article
- Molecular landscape of atherosclerotic plaque progression: insights from proteomics, single-cell transcriptomics and genomics.BMC medicine · 2025Article
- Probing the binding hypothesis of Smad3 modulators by molecular dynamic simulations for Atherosclerosis Cardiovascular Disease (ASCVD).PloS one · 2025Article
- The Genetics of Human Congenital Coronary Vascular Anomalies.Advances in experimental medicine and biology · 2024Article
- Review
- Identification of miR-143-3p as a diagnostic biomarker in gastric cancer.BMC medical genomics · 2023Article
- Discovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell Phenotype.Circulation research · 2023Article
- TGFβ signaling pathways in human health and disease.Frontiers in molecular biosciences · 2023Review
- Aortic Cellular Diversity and Quantitative Genome-Wide Association Study Trait Prioritization Through Single-Nuclear RNA Sequencing of the Aneurysmal Human Aorta.Arteriosclerosis, thrombosis, and vascular biology · 2022Article
- Effects of Coronary Artery Disease-Associated Variants on Vascular Smooth Muscle Cells.Circulation · 2022Article
- Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque.Nature cardiovascular research · 2022Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Although numerous genetic loci have been associated with coronary artery disease (CAD) with genome wide association studies, efforts are needed to identify the causal genes in these loci and link them into fundamental signaling pathways. Recent studies have investigated the disease mechanism of CAD associated gene SMAD3, a central transcription factor (TF) in the TGFβ pathway, investigating its role in smooth muscle biology. In vitro studies in human coronary artery smooth muscle cells (HCASMC) revealed that SMAD3 modulates cellular phenotype, promoting expression of differentiation marker genes while inhibiting proliferation. RNA sequencing and chromatin immunoprecipitation sequencing studies in HCASMC identified downstream genes that reside in pathways which mediate vascular development and atherosclerosis processes in this cell type. HCASMC phenotype, and gene expression patterns promoted by SMAD3 were noted to have opposing direction of effect compared to another CAD associated TF, TCF21. At sites of SMAD3 and TCF21 colocalization on DNA, SMAD3 binding was inversely correlated with TCF21 binding, due in part to TCF21 locally blocking chromatin accessibility at the SMAD3 binding site. Further, TCF21 was able to directly inhibit SMAD3 activation of gene expression in transfection reporter gene studies. In contrast to TCF21 which is protective toward CAD, SMAD3 expression in HCASMC was shown to be directly correlated with disease risk. We propose that the pro-differentiation action of SMAD3 inhibits dedifferentiation that is required for HCASMC to expand and stabilize disease plaque as they respond to vascular stresses, counteracting the protective dedifferentiating activity of TCF21 and promoting disease risk.
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