Published online before print November 6, 2003, doi: 10.1161/01.ATV.0000105889.29687.CC
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© 2004 American Heart Association, Inc.
Thrombosis |
Regulation of Endogenous Reactive Oxygen Species in Platelets Can Reverse Aggregation
From the Department of Pharmacology (P.C., A.M.), Georgetown University Medical Center, Washington, DC, and the Whitaker Cardiovascular Institute and Evans Department of Medicine (J.E.F.), Boston University School of Medicine, Boston, Mass.
Correspondence to Jane E. Freedman, 700 Albany Street W507, Boston MA 02118. E-mail Freedmaj{at}bu.edu
Objective— While much is known about the normal activation of platelets, there have been few observations demonstrating reversibility of the aggregation process. Inhibition of phosphoinositide 3-kinase (PI3-kinase) has been shown to cause platelet disaggregation. In addition, NO is a known potent inhibitor of platelet function. In this study, the role of PI3-kinase in the regulation of endogenous platelet NO and the relevance to platelet function was determined.
Methods and Results— Incubation of platelets with PI3-kinase inhibitors led to a dose-dependent increase in platelet NO and cGMP levels that were temporally related to the period of platelet disaggregation. Addition of ferroheme myoglobin eliminated both the augmented NO release and disaggregation. PI3-kinase inhibition decreased the functional activation of NADPH oxidase and this corresponded to decreased superoxide release. To confirm these findings, platelets from NOS III-deficient mice were studied. These platelets did not release NO, and PI3-kinase inhibition led to decreased superoxide but not platelet disaggregation.
Conclusion— Overall, these results indicate that platelet-derived NO contributes to the process of platelet disaggregation. PI3-kinase plays a role in regulating NADPH oxidase-generated superoxide in platelets and, by altering the bioactivity of platelet NO, may be a potential method for reversing platelet aggregation and thrombus formation.
Key Words: NADPH oxidase • nitric oxide • phosphoinositide 3-kinase • platelets • superoxide
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