FURIN Expression in Vascular Endothelial Cells Is Modulated by a Coronary Artery Disease–Associated Genetic Variant and Influences Monocyte Transendothelial Migration

Abstract

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.

SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy

“…The heart shows high levels of ACE2 , but low levels of TMPRSS2 expression, which calls into question the mechanism of injury and myocarditis observed in severe cases of COVID-19. However, a polybasic furin cleavage site has been recently identified in the SARS-CoV-2 spike protein [41] ; furin-like proteases that may contribute to SARS-CoV-2 spike protein processing are more ubiquitously expressed and may explain an expanded cell and tissue tropism of SARS-CoV-2 compared to SARS-CoV, which lacks this site [41] , [42] , [43] .

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Obesity and COVID-19: Molecular Mechanisms Linking Both Pandemics

“…Furin expression levels correlate with atherogenesis [157]. Recently, it has been revealed that expressed furin in vascular endothelial cells promotes the NF-κB activity; the expression of VCAM-1, MCP-1, and monocyte-endothelial adhesion; and transmigration [158], which results in further inflammation and damage of vascular endothelium. In addition to furin, vascular endothelium also highly expresses the ACE2 receptor [110] and the priming protease TMPRSS2 [159], which make the endothelium of patients with obesity highly susceptible to SARS-CoV-2 infection.…”

Tissue Proteases and Immune Responses: Influencing Factors of COVID-19 Severity and Mortality

“…For instance, the coronary artery disease genetic variant rs17514846 increases furin expression and this may be related to reduced monocyte migration and proliferation in humans [ 56 ]. Accordingly, the variant rs17514846 at the 15q26.1 locus was recently linked to higher circulating monocyte chemoattractant protein-1 (MCP-1) levels and greater carotid intima-media thickness in comparison with non-carrier individuals [ 57 ]. The same study also demonstrated that furin knockdown in vascular endothelial cells reduces endothelial cell-mediated inflammation as well as monocyte adhesion to and transmigration through these cells [ 57 ].…”

“…Accordingly, the variant rs17514846 at the 15q26.1 locus was recently linked to higher circulating monocyte chemoattractant protein-1 (MCP-1) levels and greater carotid intima-media thickness in comparison with non-carrier individuals [ 57 ]. The same study also demonstrated that furin knockdown in vascular endothelial cells reduces endothelial cell-mediated inflammation as well as monocyte adhesion to and transmigration through these cells [ 57 ]. A similar profile was observed in mice with atherosclerotic lesions treated with furin inhibitors (α-1-PDX, RP-070) [ 68 ].…”