Elsevier

Atherosclerosis

Volume 230, Issue 2, October 2013, Pages 185-190
Atherosclerosis

Increased monocyte adhesion by endothelial expression of VCAM-1 missense variation in vitro

https://doi.org/10.1016/j.atherosclerosis.2013.07.039Get rights and content
Under a Creative Commons license
open access

Highlights

  • Variant VCAM-1 forms significantly affect monocyte adherence to endothelial cells.

  • VCAM-1 forms 318F, 555V and 716L increase monocyte adherence.

  • VCAM-1 variants may explain interindividually different atherosclerotic phenotypes.

Abstract

Objective

In whole genome and single gene analyses, genetic variation at the vascular cell adhesion molecule-1 (VCAM-1) locus has been associated with inflammatory disease and stroke in sickle cell anaemia. In the current work, we investigated the functional impact of VCAM-1 missense variants and their effect on cell–cell adhesion.

Methods and results

To determine the functional in vitro relevance of five missense VCAM-1 variants (S318F; T384A; G413A; L555V; I716L), we generated wild type and single variant VCAM-1 forms [318F, 384A, 413A, 555V, 716L] in EA.hy926 endothelial cells. Real-time PCR, western blot and ELISA analyses revealed significant differences in mRNA and protein levels for VCAM-1 variants. Monocytic cell lines THP-1 and U937 showed significantly increased adhesion to endothelial cells overexpressing VCAM-1 forms 318F, 555V and 716L compared to those overexpressing wild type VCAM-1 (p < 0.05).

Conclusions

VCAM-1-dependent cell adhesion to endothelial cells in vitro is significantly increased when expressing VCAM-1 missense mutations 318F, 555V and 716L. The underlying mechanism involves altered VCAM-1 protein levels and function. This observation may be of particular relevance for chronic inflammatory pathophysiologic conditions involving cell–cell adhesion such as atherosclerosis and other proinflammatory conditions.

Keywords

Cardiovascular disease
Functional analyses
Missense variants
Vascular cell adhesion protein-1
Monocyte adhesion

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