Stimulatory roles of nitric-oxide synthase 3 and guanylyl cyclase in platelet activation.
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.
Marjanovic
Jasna A
JA
Department of Pharmacology, College of Medicine, University of Illinois, Chicago, 60612, USA.
Li
Zhenyu
Z
Stojanovic
Aleksandra
A
Du
Xiaoping
X
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D002478:Cells, Cultured; D002712:Chlorides; D005290:Ferric Compounds / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology; D006162:Guanylate Cyclase; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D013927:Thrombosis / Q000139:chemically induced / Q000201:enzymology
D002712:Chlorides; D005290:Ferric Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C024555:ferric chloride