التفاصيل البيبلوغرافية
| العنوان: |
Influence of a Coronary Artery Disease-Associated Genetic Variant on FURIN Expression and Effect of Furin on Macrophage Behavior. |
| المؤلفون: |
Guojun Zhao, Wei Yang, Jingchun Wu, Bairu Chen, Xu Yang, Junhui Chen, David G. McVey, Catherine Andreadi, Peng Gong, Tom R. Webb, Nilesh J. Samani, Shu Ye |
| سنة النشر: |
2018 |
| المجموعة: |
University of Leicester: Figshare |
| مصطلحات موضوعية: |
Uncategorized, coronary artery disease, furin, macrophages, monocytes, polymorphism, single nucleotide |
| الوصف: |
OBJECTIVE: Genome-wide association studies have revealed a robust association between genetic variation on chromosome 15q26.1 and coronary artery disease (CAD) susceptibility; however, the underlying biological mechanism is still unknown. The lead CAD-associated genetic variant (rs17514846) at this locus resides in the FURIN gene. In advanced atherosclerotic plaques, furin is expressed primarily in macrophages. We investigated whether this CAD-associated variant alters FURIN expression and whether furin affects monocyte/macrophage behavior. APPROACH AND RESULTS: A quantitative reverse transcription polymerase chain reaction analysis showed that leukocytes from individuals carrying the CAD risk allele of rs17514846 had increased FURIN expression. A chromatin immunoprecipitation assay revealed higher RNA polymerase II occupancy in the FURIN gene in mononuclear cells of individuals carrying this allele. A reporter gene assay in transiently transfected monocytes/macrophages indicated that the CAD risk allele had higher transcriptional activity than the nonrisk allele. An analysis of isogenic monocyte cell lines created by CRISPR-mediated genome editing showed that isogenic cells with the A/A genotype for rs17514846 had higher FURIN expression levels than the isogenic cells with the C/C genotype. An electrophoretic mobility shift assay exhibited preferential binding of a nuclear protein to the risk allele. Studies of monocytes/macrophages with lentivirus-mediated furin overexpression or shRNA-induced furin knockdown showed that furin overexpression promoted monocyte/macrophage migration, increased proliferation, and reduced apoptosis whereas furin knockdown had the opposite effects. CONCLUSIONS: Our study shows that the CAD-associated genetic variant increases FURIN expression and that furin promotes monocyte/macrophage migration and proliferation while inhibiting apoptosis, providing a biological mechanism for the association between variation at the chromosome 15q26.1 locus and CAD risk. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
unknown |
| Relation: |
2381/42665; https://figshare.com/articles/journal_contribution/Influence_of_a_Coronary_Artery_Disease-Associated_Genetic_Variant_on_FURIN_Expression_and_Effect_of_Furin_on_Macrophage_Behavior_/10214213 |
| الاتاحة: |
https://figshare.com/articles/journal_contribution/Influence_of_a_Coronary_Artery_Disease-Associated_Genetic_Variant_on_FURIN_Expression_and_Effect_of_Furin_on_Macrophage_Behavior_/10214213 |
| Rights: |
CC BY-NC-ND 4.0 |
| رقم الانضمام: |
edsbas.403EEFE9 |
| قاعدة البيانات: |
BASE |