(Circulation. 1995;92:3304-3311.)
© 1995 American Heart Association, Inc.
Articles |
Peptido-Leukotrienes Are Potent Agonists of von Willebrand Factor Secretion and P-Selectin Surface Expression in Human Umbilical Vein Endothelial Cells
From the Hematology-Oncology Division, Brigham and Women's Hospital, and Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Mass.
Correspondence to Bruce M. Ewenstein, MD, PhD, Hematology-Oncology Division, or Charles N. Serhan, PhD; new address: Center for Experimental Therapeutics and Reperfusion Injury, 75 Francis St, Boston, MA 02115.
Background The peptido-leukotrienes (LTs) and lipoxins (LX) are produced by platelets through the transcellular conversion of leukocyte-derived LTA4 at sites of vascular inflammation and injury, such as during coronary artery balloon angioplasty. We studied the actions of these eicosanoids on vascular endothelium.
Methods and Results We found that stimulation of cultured human umbilical vein endothelial cells (EC) with LTC4 and LTD4 resulted in the release of high-molecular-weight multimers of von Willebrand factor (vWF) in a concentration- and time-dependent fashion, as measured by ELISA. Neither LXA4 nor LXB4 stimulated vWF release. LTC4 and LTD4 also stimulated a rapid increase in the surface expression of P-selectin indicated by increased binding of anti–P-selectin monoclonal antibody–coated beads. Fluorescence cytometry detected prolonged peaks of [Ca2+]i in EC in response to concentrations of thrombin and LTD4 that induce near-maximal vWF secretion. In contrast, concentrations of LTC4 that induce similar levels of vWF secretion produced only asynchronous oscillations of [Ca2+]i in most EC and rarely induced prolonged peaks of [Ca2+]i. Depletion of external Ca2+ had no apparent impact on LT-stimulated [Ca2+]i transients and vWF secretion, implicating an intracellular pool as the source of this response. Staurosporine, sphingosine, and H-7 each had only modest effects on peptido-LT–induced vWF secretion, suggesting that protein kinase C is not a primary mediator of peptido-LT–induced exocytosis. Inhibitors of cyclooxygenase and platelet-activating factor had no effect on peptido-LT–mediated vWF secretion.
Conclusions Through the induction of vWF secretion and P-selectin surface expression, peptido-LTs are likely to play an important role in the interrelated processes of hemostasis and inflammation.
Key Words: von Willebrand factor • secretion • leukotriene • eicosanoid • transcellular metabolism
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