Down-regulated RGS5 by genetic variants impairs endothelial cell function and contributes to coronary artery disease
| Autor: | Xiao-Li Tian, Xiuying Liu, Yang Li, Yingchun Han, Jian Guo, Jie Du, Han Yan, Cui-Fang Zhang |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Candidate gene Endothelium THP-1 Cells Physiology Down-Regulation Genome-wide association study Single-nucleotide polymorphism Coronary Artery Disease Biology Polymorphism Single Nucleotide Transcriptome Physiology (medical) medicine Animals Humans Carotid Stenosis Genetic Predisposition to Disease Gene Aged Genetic association Gene Expression Profiling NF-kappa B Endothelial Cells Middle Aged Chemokine CXCL12 Mice Inbred C57BL Disease Models Animal HEK293 Cells Phenotype medicine.anatomical_structure Case-Control Studies Cancer research Female Cardiology and Cardiovascular Medicine Candidate Disease Gene RGS Proteins Genome-Wide Association Study |
| Zdroj: | Cardiovascular Research. 117:240-255 |
| ISSN: | 1755-3245 0008-6363 |
| Popis: | Aims Genetic contribution to coronary artery disease (CAD) remains largely unillustrated. Although transcriptomic profiles have identified dozens of genes that are differentially expressed in normal and atherosclerotic vessels, whether those genes are genetically associated with CAD remains to be determined. Here, we combined genetic association studies, transcriptome profiles and in vitro and in vivo functional experiments to identify novel susceptibility genes for CAD. Methods and results Through an integrative analysis of transcriptome profiles with genome-wide association studies for CAD, we obtained 18 candidate genes and selected one representative single nucleotide polymorphism (SNP) for each gene for multi-centred validations. We identified an intragenic SNP, rs1056515 in RGS5 gene (odds ratio = 1.17, 95% confidence interval =1.10–1.24, P = 3.72 × 10−8) associated with CAD at genome-wide significance. Rare genetic variants in linkage disequilibrium with rs1056515 were identified in CAD patients leading to a decreased expression of RGS5. The decreased expression was also observed in atherosclerotic vessels and endothelial cells treated by various cardiovascular risk factors. Through siRNA knockdown and adenoviral overexpression, we further showed that RGS5 regulated endothelial inflammation, vascular remodelling, as well as canonical NF-κB signalling activation. Moreover, CXCL12, a specific downstream target of the non-canonical NF-κB pathway, was strongly affected by RGS5. However, the p100 processing, a well-documented marker for non-canonical NF-κB pathway activation, was not altered, suggesting an existence of a novel mechanism by which RGS5 regulates CXCL12. Conclusions We identified RGS5 as a novel susceptibility gene for CAD and showed that the decreased expression of RGS5 impaired endothelial cell function and functionally contributed to atherosclerosis through a variety of molecular mechanisms. How RGS5 regulates the expression of CXCL12 needs further studies. |
| Databáze: | OpenAIRE |
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