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J. Cell Biol. 157 (1): 173-184

Copyright © 2002 by the Rockefeller University Press.


Article

PECAM-1 (CD31) regulates a hydrogen peroxide–activated nonselective cation channel in endothelial cells

Guangju Ji3, Christopher D. O'Brien1, Morris Feldman3, Yefim Manevich2, Poay Lim1, Jing Sun1, Steven M. Albelda1, and Michael I. Kotlikoff3

1 Division of Pulmonary, Allergy, and Critical Care Medicine
2 Institute for Environmental Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
3 Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853

Address correspondence to Christopher D. O'Brien, Dept. of Pulmonary/Critical Care, University of Pennsylvania, 838 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: (215) 746-6709. Fax: (215) 573-4469. E-mail: christoo{at}mail.med.UPENN.edu

Abstract: Hydrogen peroxide (H2O2) released by neutrophils is an important mediator of endothelial cell (EC) injury and vascular inflammation via its effect on EC-free Ca2+, [Ca2+]i. Although the underlying mechanisms are not well understood, platelet endothelial cell adhesion molecule (PECAM)-1/CD-31 is a critical modulator of neutrophil–EC transmigration. PECAM-1 is also known to regulate EC calcium signals and to undergo selective tyrosine phosphorylation. Here, we report that PECAM-1 molecules transduce EC responses to hydrogen peroxide. In human umbilical vein EC and REN cells (a PECAM-1–negative EC-like cell line) stably transfected with PECAM-1 (RHP), noncytolytic H2O2 exposure (100–200 µM H2O2) activated a calcium-permeant, nonselective cation current, and a transient rise in [Ca2+]i of similar time course. Neither response was observed in untransfected REN cells, and H2O2-evoked cation current was ablated in REN cells transfected with PECAM-1 constructs mutated in the cytoplasmic tyrosine–containing domain. The PECAM-dependent H2O2 current was inhibited by dialysis of anti–PECAM-1 cytoplasmic domain antibodies, required Src family tyrosine kinase activity, was independent of inositol trisphosphate receptor activation, and required only an intact PECAM-1 cytoplasmic domain. PECAM-1–dependent H2O2 currents and associated [Ca2+]i transients may play a significant role in regulating neutrophil–endothelial interaction, as well as in oxidant-mediated endothelial response and injury.

Key Words: hydrogen peroxide; capacitative current; calcium; tyrosine kinase; ion channels


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