Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an NF-kappaB-dependent manner.
The involvement of platelets in the pathogenesis of atherosclerosis has recently gained much attention. Platelet factor 4 (PF4), a platelet-specific chemokine released on platelet activation, has been localized to atherosclerotic lesions, including macrophages and endothelium. In this report, we demonstrate that E-selectin, an adhesion molecule involved in atherogenesis, is up-regulated in human umbilical vein endothelial cells exposed to PF4. Induction of E-selectin RNA is time and dose dependent. Surface expression of E-selectin, as measured by flow cytometry, is also increased by PF4. PF4 induces E-selectin expression by activation of transcriptional activity. Activation of nuclear factor-kappaB is critical for PF4-induced E-selectin expression, as demonstrated by promoter activation studies and electrophoretic mobility shift assays. Further, we have identified the low-density lipoprotein receptor-related protein as the cell surface receptor mediating this effect. These results demonstrate that PF4 is able to increase expression of E-selectin by endothelial cells and represents another potential mechanism by which platelets may participate in atherosclerotic lesion progression.
Yu
Guangyao
G
University of Pennsylvania, 207 John Morgan, Philadelphia, PA 19104, USA.
Rux
Ann H
AH
Ma
Peihong
P
Bdeir
Khalil
K
Sachais
Bruce S
BS
D001161:Arteriosclerosis / Q000209:etiology; D001792:Blood Platelets / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010978:Platelet Factor 4 / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000235:genetics
D019040:E-Selectin; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D016328:NF-kappa B; D010978:Platelet Factor 4; D012313:RNA