Rapid upregulation of endothelial P-selectin expression via reactive oxygen species generation.
Endothelial cell ICAM-1 upregulation in response to TNF-alpha is mediated in part by reactive oxygen species (ROS) generated by the endothelial membrane-associated NADPH oxidase and occurs maximally after 4 h as the synthesis of new protein is required. However, thrombin-stimulated P-selectin upregulation is bimodal, the first peak occurring within minutes. We hypothesize that this early peak, which results from the release of preformed P-selectin from within Weibel-Palade bodies, is mediated in part by ROS generated from the endothelial membrane-associated xanthine oxidase. We found that this rapid expression of P-selectin on the surface of endothelial cells was accompanied by qualitatively parallel increases in ROS generation. Both P-selectin expression and ROS generation were inhibited, dose dependently, by the exogenous administration of disparate cell-permeable antioxidants and also by the inhibition of either of the known membrane-associated ROS-generating enzymes NADPH oxidase or xanthine oxidase. This rapid, posttranslational cell signaling response, mediated by ROS generated not only by the classical NADPH oxidase but also by xanthine oxidase, may well represent an important physiological trigger of the microvascular inflammatory response.
Takano
Manabu
M
Department of Surgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Meneshian
Avedis
A
Sheikh
Emran
E
Yamakawa
Yasuhiko
Y
Wilkins
Kirsten Bass
KB
Hopkins
Elise A
EA
Bulkley
Gregory B
GB
D051943:Antennapedia Homeodomain Protein; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006490:Hemostatics / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000494:pharmacology; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism; D009687:Nuclear Proteins; D019007:P-Selectin / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D014157:Transcription Factors; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014969:Xanthine Oxidase / Q000378:metabolism
D051943:Antennapedia Homeodomain Protein; D006490:Hemostatics; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D019007:P-Selectin; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D013917:Thrombin