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dc.contributor.authorNaseem, Khalid M.*
dc.contributor.authorRiba, Rocio*
dc.contributor.authorOberprieler, Nikolaus G.*
dc.contributor.authorRoberts, Wayne*
dc.date.accessioned2009-09-14T07:18:42Z
dc.date.available2009-09-14T07:18:42Z
dc.date.issued2006
dc.identifier.citationNaseen, K.M., Riba, R., Oberprieler, N.G. and Roberts, W. (2006). Von Willebrand factor activates endothelial nitric oxide synthase in blood platelets by a GPIb-dependent mechanism. Journal of Thrombosis Haemostasis. Vol. 4, No. 12, pp. 2630-2644.en
dc.identifier.urihttp://hdl.handle.net/10454/3431
dc.descriptionNoen
dc.description.abstractBackground: The molecular regulation of endothelial nitric oxide synthase (eNOS) in blood platelets and the signalling events induced by platelet-derived NO are poorly defined. In particular, the ability of von Willebrand factor (VWF) to stimulate cyclic guanosine monophosphate (cGMP) formation in platelets has produced conflicting data. Objectives: To determine the mechanisms leading to eNOS activation and clarify the downstream signaling pathways activated by platelet-derived NO in response to VWF. Methods: We used three independent markers of NO signaling, [3H] l-citrulline production, cGMP accrual and immunoblotting of vasodilator¿stimulated phosphoprotein (VASP) to examine the NO signaling cascade in response to VWF. Results: VWF increased NO synthesis and bioavailability, as evidenced by increased [3H] l-citrulline production and cGMP accrual, respectively. VWF-induced eNOS activation was GPIb-IX-dependent and independent of integrin ¿IIbß3. cGMP formation in response to VWF required Ca2+ mobilization, Src family kinases, phosphatidylinositol 3-kinase and phospholipase C, but not protein kinase C. This suggests that a cross-talk between the signaling mechanisms regulates platelet activation and NO synthesis. VWF-induced cGMP accrual was completely blocked by apyrase and indomethacin, demonstrating an essential role for platelet-derived ADP and thromboxane A2 (TxA2). Elevated cGMP levels led to increased VASP phosphorylation at serine239 that was both protein kinase G (PKG)- and protein kinase A (PKA)-dependent. Conclusions: We demonstrate that VWF activates eNOS through a specific Ca2+-dependent GPIb receptor-signaling cascade that relies on the generation of platelet-derived ADP and TxA2. Furthermore, we provide the first evidence to suggest that platelet derived-NO/cGMP activates PKA in addition to PKG.en
dc.language.isoenen
dc.relation.isreferencedbyhttp://dx.doi.org/10.1111/j.1538-7836.2006.02195.xen
dc.subjectCyclic guanosine monophosphateen
dc.subjectNitric oxideen
dc.subjectPlateletsen
dc.subjectProtein kinase Aen
dc.subjectVon Willebrand factoren
dc.titleVon Willebrand factor activates endothelial nitric oxide synthase in blood platelets by a GPIb-dependent mechanism.en
dc.status.refereedYesen
dc.typeArticleen
dc.type.versionNo full-text available in the repositoryen


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