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J. Biol. Chem., Vol. 280, Issue 45, 37430-37438, November 11, 2005

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Stimulatory Roles of Nitric-oxide Synthase 3 and Guanylyl Cyclase in Platelet Activation^*

From the Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612

Nitric oxide (NO) stimulates soluble guanylyl cyclase and, thus, enhances cyclic guanosine monophosphate (cGMP) levels. It is a currently prevailing concept that NO inhibits platelet activation. This concept, however, does not fully explain why platelet agonists stimulate NO production. Here we show that a major platelet NO synthase (NOS) isoform, NOS3, plays a stimulatory role in platelet secretion and aggregation induced by low doses of platelet agonists. Furthermore, we show that NOS3 promotes thrombosis in vivo. The stimulatory role of NOS is mediated by soluble guanylyl cyclase and results from a cGMP-dependent stimulation of platelet granule secretion. These findings delineate a novel signaling pathway in which agonists sequentially activate NOS3, elevate cGMP, and induce platelet secretion and aggregation. Our data also suggest that NO plays a biphasic role in platelet activation, a stimulatory role at low NO concentrations and an inhibitory role at high NO concentrations.

Received for publication, June 15, 2005 , and in revised form, August 29, 2005.

^* This work was supported by NHLBI, National Institutes of Health Grants HL62350 and HL68819 (to X. D), by an American Heart Association Midwest Affiliate fellowship (to J. A. M.), and by an American Heart Association Scientist Development Award (to Z. L.). 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Ave., Rm. E403, Chicago, IL 60612. Tel.: 312-355-0237; Fax: 312-996-1225; E-mail: xdu{at}uic.edu.

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