Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells that Contribute to the Fibrous Cap
| العنوان: | Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells that Contribute to the Fibrous Cap |
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| المؤلفون: | Komal Arora, William A. Boisvert, Azad Raiesdana, Ramen Kundu, Nikitha Murthy, Nikhil Tellakula, Clint L. Miller, Karen Cheng, Ljubica Perisic, Gary K. Owens, Yiqin Xiong, Juyong Brian Kim, Vivek Nanda, Michelle D. Tallquist, Sylvia T. Nurnberg, Lars Maegdefessel, Milos Pjanic, Silvia Aldi, Thomas Quertermous, Ulf Hedin, Ivan Carcamo-Oribe |
| المصدر: | Genomics Data PLoS Genetics, Vol 11, Iss 5, p e1005155 (2015) Genomics Data, Vol 5, Iss C, Pp 36-37 (2015) PLoS Genetics |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Cancer Research, Cellular differentiation, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Biochemistry, Coronary artery disease, Transcriptome, Myoblasts, Growth Factor Receptor Gene, Mice, 0302 clinical medicine, Gene expression, Basic Helix-Loop-Helix Transcription Factors, Myocyte, GWAS, Genetics (clinical), Genetics, 0303 health sciences, Stem Cells, Fibrous cap, Gene Expression Regulation, Developmental, High-Throughput Nucleotide Sequencing, Cell Differentiation, Cell biology, Coronary heart disease, medicine.anatomical_structure, Gene Knockdown Techniques, Molecular Medicine, Stem cell, Biotechnology, Research Article, Cell type, lcsh:QH426-470, Myocytes, Smooth Muscle, Biology, 03 medical and health sciences, Precursor cell, Data in Brief, medicine, Animals, Humans, Cell Lineage, Gene, Transcription factor, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Cell Proliferation, 030304 developmental biology, Reporter gene, Fibroblasts, medicine.disease, Atherosclerosis, In vitro, Coronary arteries, lcsh:Genetics, Smooth muscle cell |
| الوصف: | Recent genome wide association studies have identified a number of genes that contribute to the risk for coronary heart disease. One such gene, TCF21, encodes a basic-helix-loop-helix transcription factor believed to serve a critical role in the development of epicardial progenitor cells that give rise to coronary artery smooth muscle cells (SMC) and cardiac fibroblasts. Using reporter gene and immunolocalization studies with mouse and human tissues we have found that vascular TCF21 expression in the adult is restricted primarily to adventitial cells associated with coronary arteries and also medial SMC in the proximal aorta of mouse. Genome wide RNA-Seq studies in human coronary artery SMC (HCASMC) with siRNA knockdown found a number of putative TCF21 downstream pathways identified by enrichment of terms related to CAD, including “vascular disease,” “disorder of artery,” and “occlusion of artery,” as well as disease-related cellular functions including “cellular movement” and “cellular growth and proliferation.” In vitro studies in HCASMC demonstrated that TCF21 expression promotes proliferation and migration and inhibits SMC lineage marker expression. Detailed in situ expression studies with reporter gene and lineage tracing revealed that vascular wall cells expressing Tcf21 before disease initiation migrate into vascular lesions of ApoE-/- and Ldlr-/- mice. While Tcf21 lineage traced cells are distributed throughout the early lesions, in mature lesions they contribute to the formation of a subcapsular layer of cells, and others become associated with the fibrous cap. The lineage traced fibrous cap cells activate expression of SMC markers and growth factor receptor genes. Taken together, these data suggest that TCF21 may have a role regulating the differentiation state of SMC precursor cells that migrate into vascular lesions and contribute to the fibrous cap and more broadly, in view of the association of this gene with human CAD, provide evidence that these processes may be a mechanism for CAD risk attributable to the vascular wall. Author Summary Coronary artery disease (CAD) is responsible for the majority of deaths in the Western world, and is due in part to environmental and metabolic factors. However, half of the risk for developing heart disease is genetically predetermined. Genome-wide association studies in human populations have identified over 100 sites in the genome that appear to be associated with CAD, however, the mechanisms by which variation in these regions are responsible for predisposition to CAD remain largely unknown. We have begun to study a gene that contributes to CAD risk, the TCF21 gene. Through genomic studies we show that this gene is involved in processes related to alterations in vascular gene expression, and in particular those related to the smooth muscle cell biology. With cell culture models, we show that TCF21 regulates the differentiation state of this cell type, which is believed critical for vascular disease. Using mouse genetic models of atherosclerotic vascular disease we provide evidence that this gene is expressed in precursor cells that migrate into the disease lesions and contribute to the formation of the fibrous cap that is believed to stabilize these lesions and prevent heart attacks. |
| تدمد: | 2213-5960 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::672adb5a6b16e7780264dd7c395c3395Test https://pubmed.ncbi.nlm.nih.gov/26090325Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....672adb5a6b16e7780264dd7c395c3395 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22135960 |
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