ARFGEF2 Knockdown Enhances TNF-α Induced Endothelial Expression of the Cell Adhesion Molecules VCAM1 and ICAM1

Dworkis, Daniel A. and Klings, Elizabeth S. and Shenouda, Sherene M. and Solovieff, Nadia and Melista, Efthymia and Giovannucci, Carl and Safaya, Surinder and Li, Guihua and Vita, Joseph A. and Steinberg, Martin H. and Baldwin, Clinton T. (2013) ARFGEF2 Knockdown Enhances TNF-α Induced Endothelial Expression of the Cell Adhesion Molecules VCAM1 and ICAM1. Open Journal of Blood Diseases, 03 (01). pp. 25-31. ISSN 2164-3180

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Abstract

Sickle cell anemia (SCA) is an autosomal-recessive hemoglobinopathy with a highly variable phenotype. Multiple clinical complications are characteristic of SCA including inflammatory and oxidant damage to both small and large blood vessels, hemolysis, vasoocclusion, and premature mortality. The overall severity of SCA is affected by multiple genetic modifier loci, including ARFGEF2, a gene known to modify TNF-α receptor release from human endothelial cells. In this report, we examine the effect of siRNA mediated knockdown of ARFGEF2 inhuman pulmonary artery endothelial cells and report that TNF-α induced expression of ICAM1 and VCAM1, both important mediators of endo-thelial-leukocyte adhesion, is significantly enhanced after ARFGEF2 knockdown. Levels of ICAM-1 protein are also increased in TNF-α treated endothelial cells after ARFGEF2 knockdown; the increased ICAM-1 appears to be localized in the cytoplasm. IL-1β stimulation of endothelial cells without ARFGEF2 produced enhanced ICAM1 expression only. Additionally, ARFGEF2 knockdown distinctly altered endothelial cell morphology. Large-vessel pathology in SCA is believed to begin with endothelial activation by inflammatory cytokines and adhesion of sickle erythrocytes and leukocytes, leading to a progressive vasculopathy characterized by smooth muscle cell migration and proliferation. Understanding how variability in the function of ARFGEF2 alters the response of pulmonary vasculature to TNF-α might suggest new targets for SCA treatment.

Item Type: Article
Subjects: STM Digital > Medical Science
Depositing User: Unnamed user with email support@stmdigital.org
Date Deposited: 10 Apr 2023 09:02
Last Modified: 12 Aug 2024 12:05
URI: http://research.asianarticleeprint.com/id/eprint/542

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