FURIN Expression in Vascular Endothelial Cells Is Modulated by a Coronary Artery Disease-Associated Genetic Variant and Influences Monocyte Transendothelial Migration
journal contributionposted on 2020-06-11, 12:01 authored by Xu Yang, Wei Yang, David G McVey, Guojun Zhao, Jinfu Hu, Robin N Poston, Meixia Ren, Karin Willeit, Stefan Coassin, Johann Willeit, Thomas R Webb, Nilesh J Samani, Manuel Mayr, Stefan Kiechl, Shu Ye
Background: Genome-wide association studies have shown an association between the single-nucleotide polymorphism rs17514846 on chromosome 15q26.1 and coronary artery disease susceptibility. The underlying biological mechanism is, however, not fully understood. rs17514846 is located in the FES Upstream Region (FURIN) gene, which is expressed in vascular endothelial cells (ECs). We investigated whether rs17514846 has an influence on FURIN expression in ECs and whether FURIN affects EC behavior. Methods and Results: Quantitative reverse transcription–polymerase chain reaction analysis showed that cultured vascular ECs from individuals carrying the coronary artery disease risk allele of rs17514846 had higher FURIN expression than cells from noncarriers. In support, luciferase reporter analyses in ECs indicated that the risk allele had higher transcriptional activity than the nonrisk allele. Electrophoretic mobility shift assays using EC nuclear protein extracts detected a DNA-protein complex with allele-specific differential binding of a nuclear protein. Knockdown of FURIN in ECs reduced endothelin-1 secretion, nuclear factor-κB activity, vascular cell adhesion molecule-1, and MCP1 (monocyte chemotactic protein-1) expression and monocyte-endothelial adhesion and transmigration. A population-based study showed an association of the rs17514846 risk allele with higher circulating MCP1 levels and greater carotid intima-media thickness. Conclusions: The coronary artery disease risk variant at the 15q26.1 locus modulates FURIN expression in vascular ECs. FURIN levels in ECs affect monocyte-endothelial adhesion and migration.
We are thankful for the support of the British Heart Foundation (BHF) (PG/16/9/31995, RG/16/13/32609, RG/19/9/34655, PG/18/73/34059, and SP/19/2/344612) and the National Natural Science Foundation of China (81370202 and 81800364). This work falls under the portfolio of research conducted within the National Institute for Health Research Leicester Biomedical Research Centre. Dr Mayr is a BHF Chair Holder (CH/16/3/32406) with BHF program grant support (RG/16/14/32397). The research was also supported by the National Institute of Health Research Biomedical Research Centre, based at Guy's and St Thomas’ National Health Service Foundation Trust and King's College London, in partnership with King's College Hospital and by the excellence initiative VASCage (Centre for Promoting Vascular Health in the Ageing Community), an R&D K‐Centre (COMET program: Competence Centers for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg, and Vienna. Dr Willeit was supported by the Translational‐Research‐Programme grant “Tyrol Score,” funded by the “Land Tirol.”
CitationJournal of the American Heart Association, (2020), 9(4)
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