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J. Biol. Chem., Vol. 281, Issue 24, 16333-16339, June 16, 2006

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A Phosphoinositide 3-Kinase-AKT-Nitric Oxide-cGMP Signaling Pathway in Stimulating Platelet Secretion and Aggregation^*

Aleksandra Stojanovic, Jasna A. Marjanovic¹, Viktor M. Brovkovych, Xiaoding Peng, Nissim Hay, Randal A. Skidgel, and Xiaoping Du²

From the Department of Pharmacology and Department of Biochemistry and Molecular Biology, University of Illinois College of Medicine, Chicago, Illinois 60612

Phosphoinositide 3-kinase (PI3K) and Akt play important roles in platelet activation. However, the downstream mechanisms mediating their functions are unclear. We have recently shown that nitric-oxide (NO) synthase 3 and cGMP-dependent protein kinase stimulate platelet secretion and aggregation. Here we show that PI3K-mediated Akt activation plays an important role in agonist-stimulated platelet NO synthesis and cGMP elevation. Agonist-induced elevation of NO and cGMP was inhibited by Akt inhibitors and reduced in Akt-1 knock-out platelets. Akt-1 knock-out or Akt inhibitor-treated platelets showed reduced platelet secretion and aggregation in response to low concentrations of agonists, which can be reversed by low concentrations of 8-bromo-cGMP or sodium nitroprusside (an NO donor). Similarly, PI3K inhibitors diminished elevation of cGMP and inhibited platelet secretion and the second wave platelet aggregation, which was also partially reversed by 8-bromo-cGMP. These results indicate that the NO-cGMP pathway is an important downstream mechanism mediating PI3K and Akt signals leading to platelet secretion and aggregation. Conversely, the PI3K-Akt pathway is the major upstream mechanism responsible for activating the NO-cGMP pathway in platelets. Thus, this study delineates a novel platelet activation pathway involving sequential activation of PI3K, Akt, nitric-oxide synthase 3, sGC, and cGMP-dependent protein kinase.

Received for publication, November 17, 2005 , and in revised form, March 13, 2006.

^* This work was supported in part by NHLBI, National Institutes of Health Grants HL62350 and HL68819 (to X. D.) and HL60678 (to R. A. S). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Recipient of an American Heart Association Midwest Affiliate predoctoral fellowship.

² To whom correspondence should be addressed: Dept. of Pharmacology, University of Illinois College of Medicine, 835 South Wolcott Ave., Chicago, IL 60612. Tel.: 312-355-0237; Fax: 312-996-1225; E-mail: xdu{at}uic.edu.

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