The Journal of Experimental Medicine
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Published online 26 January 2004 doi:10.1084/jem.20030694
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 3, 347-356
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Insulin Induces the Release of Vasodilator Compounds From Platelets by a Nitric Oxide–G Kinase–VAMP-3–dependent Pathway

Voahanginirina Randriamboavonjy1, Jürgen Schrader2, Rudi Busse1, and Ingrid Fleming1

1 Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, D-60590 Frankfurt am Main, Germany
2 Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, D-40225 Düsseldorf, Germany

Address correspondence to Ingrid Fleming, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W.G.-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. Phone: 49-69-6301-6972; Fax: 49-69-6301-7668; email: fleming{at}em.uni-frankfurt.de

Insulin-induced vasodilatation is sensitive to nitric oxide (NO) synthase (NOS) inhibitors. However, insulin is unable to relax isolated arteries or to activate endothelial NOS in endothelial cells. Since insulin can enhance platelet endothelial NOS activity, we determined whether insulin-induced vasodilatation can be attributed to a NO-dependent, platelet-mediated process.

Insulin failed to relax endothelium-intact rings of porcine coronary artery. The supernatant from insulin-stimulated human platelets induced complete relaxation, which was prevented by preincubation of platelets with a NOS inhibitor, the soluble guanylyl cyclase inhibitor, NS 2028, or the G kinase inhibitor, KT 5823, and was abolished by an adenosine A2A receptor antagonist. Insulin induced the release of adenosine trisphosphate (ATP), adenosine, and serotonin from platelet-dense granules in a NO-dependent manner. This response was not detected using insulin-stimulated platelets from endothelial NOS-/- mice, although a NO donor elicited ATP release. Insulin-induced ATP release from human platelets correlated with the association of syntaxin 2 with the vesicle-associated membrane protein 3 but was not associated with the activation of {alpha}IIbß3 integrin. Thus, insulin elicits the release of vasoactive concentrations of ATP and adenosine from human platelets via a NO–G kinase–dependent signaling cascade. The mechanism of dense granule secretion involves the G kinase–dependent association of syntaxin 2 with vesicle-associated membrane protein 3.

Key Words: {alpha}IIbß3 integrin • adenosine • eNOS knockout mice • serotonin • syntaxin 2

Abbreviations used in this paper: ACD, acid citrate dextrose; ADP, adenosine diphosphate; AMPK, adenosine monophosphate–activated protein kinase; ATP, adenosine trisphosphate; CPT, cylcopentyl-theophylline; CSC, 8-(3-chlorostyryl)caffeine; cyclic GMP, guanosine-3',5' cyclic monophosphate; DETA-NONOate, diethylamine nonoate; eNOS, endothelial NOS; L-NA, N{omega}nitro-L-arginine; NO, nitric oxide; NOS, NO synthase; SNARE, N-ethylmaleimide–sensitive factor attachment protein receptor; Sp-cGMPS, guanosine-3',5' cyclic monophosphorothioate, Sp isomer; t-SNARE, target membrane SNARE; VAMP, vesicle-associated membrane protein; VASP, vasodilator-stimulated phosphoprotein.


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