TITLE:
ARFGEF2 Knockdown Enhances TNF-α Induced Endothelial Expression of the Cell Adhesion Molecules VCAM1 and ICAM1
AUTHORS:
Daniel A. Dworkis, Elizabeth S. Klings, Sherene M. Shenouda, Nadia Solovieff, Efthymia Melista, Carl Giovannucci, Surinder Safaya, Guihua Li, Joseph A. Vita, Martin H. Steinberg, Clinton T. Baldwin
KEYWORDS:
Cell Adhesion Molecules; Endothelium; Hemoglobin; Inflammation; Sickle Cell Disease
JOURNAL NAME:
Open Journal of Blood Diseases,
Vol.3 No.1,
March
29,
2013
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.