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

Xiaoping Du,Zhenyu Li,Jasna A. Marjanovic,Aleksandra Stojanovic

doi:10.1074/jbc.m506518200

Abstract

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.

Highlights

A major advance in the field of vascular biology in the last century was the discovery of the vessel dilator, nitric oxide (NO) [7,8,9]
We propose a new concept that NO plays a biphasic role in platelet activation; low concentrations of NO promote platelet secretion and aggregation, but high concentrations of NO, as previously reported, inhibit platelet activation
To examine the effect of NOS3 in platelet activation induced by other agonists, platelets were exposed to the thromboxane A2 analog U46619 or collagen

Summary

Introduction

A major advance in the field of vascular biology in the last century was the discovery of the vessel dilator, nitric oxide (NO) [7,8,9]. In this study we show that the major NOS isoform expressed in platelets, NOS3, plays a stimulatory role in low dose agonist-induced platelet activation and promotes in vivo thrombotic response in an injuryinduced arterial thrombosis model.

Results

Conclusion