ARFGEF2 Knockdown Enhances TNF-α Induced Endothelial Expression of the Cell Adhesion Molecules VCAM1 and ICAM1Report as inadecuate




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Sickle cell anemia SCAis an autosomal-recessive hemoglobinopathy with a highly variable phenotype. Multipleclinical complications are characteristic of SCA including inflammatory andoxidant damage to both small and large blood vessels, hemolysis, vasoocclusion,and premature mortality. The overall severity of SCA is affected by multiplegenetic modifier loci, including ARFGEF2,a gene known to modify TNF-α receptorrelease from human endothelial cells. In this report, we examine the effect ofsiRNA mediated knockdown of ARFGEF2 inhuman pulmonary artery endothelialcells and report that TNF-α inducedexpression of ICAM1 and VCAM1, both important mediators of endo-thelial-leukocyte adhesion, issignificantly enhanced after ARFGEF2knockdown. Levels of ICAM-1 protein are also increased in TNF-α treated endothelial cells after ARFGEF2 knockdown; the increased ICAM-1appears to be localized in the cytoplasm. IL-1β stimulation of endothelial cells without ARFGEF2 produced enhanced ICAM1expression only. Additionally, ARFGEF2knockdown distinctly altered endothelial cell morphology. Large-vesselpathology in SCA is believed to begin with endothelial activation byinflammatory cytokines and adhesion of sickle erythrocytes and leukocytes, leading to a progressivevasculopathy characterized by smooth muscle cell migration and proliferation. Understanding how variability in thefunction of ARFGEF2 alters the responseof pulmonary vasculature to TNF-α might suggest new targets for SCA treatment.

KEYWORDS

Cell Adhesion Molecules; Endothelium; Hemoglobin; Inflammation; Sickle Cell Disease

Cite this paper

D. Dworkis, E. Klings, S. Shenouda, N. Solovieff, E. Melista, C. Giovannucci, S. Safaya, G. Li, J. Vita, M. Steinberg and C. Baldwin -ARFGEF2 Knockdown Enhances TNF-α Induced Endothelial Expression of the Cell Adhesion Molecules VCAM1 and ICAM1,- Open Journal of Blood Diseases, Vol. 3 No. 1, 2013, pp. 25-31. doi: 10.4236-ojbd.2013.31006.





Author: Daniel A. Dworkis, Elizabeth S. Klings, Sherene M. Shenouda, Nadia Solovieff, Efthymia Melista, Carl Giovannucci, Surinder Safaya

Source: http://www.scirp.org/



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