Nitric Oxide and Cyclic GMP Signaling

McDonald, Lee J.; Murad, Ferid

doi:10.3181/00379727-211-43950a

Cited by 205 publications

(158 citation statements)

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“…cGMP cGMP is an intracellular second messenger of NO, bradykinin and the natriuretic peptides [74]. It is produced by the activation of the enzyme guanylate cyclase and is an indirect marker of natriuretic peptide or NO production.…”

Section: Asymmetric Dimethylargininementioning

confidence: 99%

Biomarkers in pulmonary hypertension

Warwick

Thomas²,

Yates³

2008

European Respiratory Journal

137

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There have been significant recent advances in the understanding of the pathophysiology of pulmonary hypertension, and a growing number of therapeutic agents have become available to the treating physician. Traditional methods of diagnosing and monitoring this condition have comprised echocardiography and right heart catheterisation, in addition to functional measures, such as estimation of functional class and the 6-min walk test. An increasing number of biomarkers have been described that are elevated in pulmonary hypertension and which may assist the clinician in diagnosis and in the assessment of disease severity and response to treatment.The present article details the more important biomarkers, their potential applications and the evidence supporting their use.

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Section: Asymmetric Dimethylargininementioning

confidence: 99%

Biomarkers in pulmonary hypertension

Warwick

Thomas²,

Yates³

2008

European Respiratory Journal

137

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“…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). NO is a short-lived messenger molecule synthesized from L-arginine by a family of enzymes known as nitric-oxide synthases (NOS).…”

mentioning

confidence: 99%

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

Marjanovic

Stojanović

et al. 2005

Journal of Biological Chemistry

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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.Development of thrombotic diseases involves the injury or dysfunction of the blood vessel wall and activation of blood platelets (1). Upon exposure to agonists such as thrombin, ADP, collagen, and von Willebrand factor (VWF), 2 platelets become "activated" and aggregate to form primary thrombi (1, 2). Activated platelets secrete large quantities of ADP, serotonin, and other factors that amplify platelet activation and stabilize platelet aggregates (3). Activated platelets also secrete pro-coagulation, pro-inflammatory, and growth factors (3-5). Thus, platelet activation plays a major role not only in acute arterial thrombosis but also in the development of chronic vascular diseases, such as atherosclerosis, which in turn causes thrombosis (1, 6).A major advance in the field of vascular biology in the last century was the discovery of the vessel dilator, nitric oxide (NO) (7-9). NO is a short-lived messenger molecule synthesized from L-arginine by a family of enzymes known as nitric-oxide synthases (NOS). Three isoforms of NOS enzymes are known (10 -12): NOS1 (neuronal NOS), NOS2 (inducible NOS), and NOS3 (endothelial NOS). NOS3 is the major isoform known to be expressed in platelets (13). One of the major functions of NO is to stimulate soluble guanylyl cyclase (sGC) and increase the synthesis of cyclic guanosine monophosphate (cGMP) that serves as a secondary messenger regulating the function of cGMP-dependent protein kinase (PKG), cGMP-dependent ion channels, and cGMP-regulated phosphodiesterases (7). High concentrations of NO can also chemically modify (nitrosylation and nitration) proteins and, thus, affect cell functions in a cGMP-independent manner (7, 14 -16). NO is involved in diverse processes, such as smooth muscle relaxation, neurotransmission, immune responses, and inflammation (7). It has been a prevailing concept that NO, by elevating intracellular cGMP, inhibits platelet activation (8). This concept is supported by data that high concentrations of NO donor compounds inhibit platelet activation (17-19). However, the concept...

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“…Such S-nitrosylation-mediated effects are direct and independent of activation of guanylyl cyclase, which is a major target for NO and a frequent mediator of the actions of NO (13,14). Studies have revealed that nitrosothiol formation underlies the direct modifying action of NO on a number of important plasma membrane and intracellular channels for Ca 2ϩ and other ions including the N-methyl-Daspartate receptor (8), cyclic nucleotide-gated cation channel (15,16), Ca 2ϩ -activated K ϩ channel (17), L-type Ca 2ϩ channel (18), and the ryanodine receptor Ca 2ϩ release channel (19).…”

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confidence: 99%

Ca2+ Entry Activated byS-Nitrosylation

Hong

Favre²,

Patterson

et al. 1999

Journal of Biological Chemistry

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The coupling between Ca 2؉ pools and store-operated Ca 2؉ entry channels (SOCs) remains an unresolved question. Recently, we revealed that Ca 2؉ entry could be activated in response to S-nitrosylation and that this process was stimulated by Ca 2؉ entry suggested a single entry mechanism. Calyculin A-induced reorganization of the actin cytoskeleton prevented SOC but had no effect on GEA3162-induced Ca 2؉ entry. However, a single entry mechanism could account for both SOC and NO donoractivated entry if the latter reflected direct modification of the entry channel by S-nitrosylation, bypassing the normal coupling process between channels and pools. Small differences between SOC and GEA3162-activated Ba 2؉ entry and sensitivity to blockade by La 3؉ were observed, and in HEK293 cells SOC activity was observed without a response to thiol modification. It is concluded that in some cells, S-nitrosylation modifies an entry mechanism closely related to SOC and/or part of the regulatory machinery for SOC-mediated Ca 2؉ entry.

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Nitric Oxide and Cyclic GMP Signaling

Cited by 205 publications

References 0 publications

Biomarkers in pulmonary hypertension

Biomarkers in pulmonary hypertension

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

Ca2+ Entry Activated byS-Nitrosylation

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