A Stimulatory Role for cGMP-Dependent Protein Kinase in Platelet Activation

Li, Zhenyu; Xi, Xiaodong; Gu, Minghong; Feil, Robert; Ye, Richard D.; Eigenthaler, Martin; Hofmann, Franz; Du, Xiaoping

doi:10.1016/s0092-8674(02)01254-0

Cited by 248 publications

(296 citation statements)

References 44 publications

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“…29 However, other reports have negated the presence of eNOS in platelets 30 and 1 group has even provided evidence that platelet-derived NO and its second messenger, cGMP, have a stimulatory role on platelet activation. 31 Similarly, studies on the role of platelet-derived NO in thrombosis models in vivo have given conflicting results, with data in favor of A B Figure 7. The effect of dl-nebivolol, l-nebivolol, d-nebivolol, and bisoprolol on systemic blood pressure in eNOS −/− (A) and wild type (B) mice.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Momi

Caracchini

Falcinelli

et al. 2014

ATVB

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H ypertension is associated with an increased risk of arterial thrombotic events, such as stroke and myocardial infarction, 1 in which platelets are deeply involved. Previous studies have shown that β-adrenoceptor blockers reduce platelet activation and aggregation, 2 but this does not seem to be a class effect because not all β-blockers share this property. 3 dl-Nebivolol (a racemic mixture of d-and l-nebivolol) is a third-generation β 1 adrenoceptor-selective antagonist that, besides its β-blockade-mediated hypotensive effect, possesses direct vasodilatory properties through a mechanism involving the l-arginine/nitric oxide (NO) pathway. 4,5 Of the 2 enantiomers forming the racemic mixture of dl-nebivolol, d-nebivolol, which has an ≈200-fold greater affinity for β 1 -adrenoceptors than that of l-nebivolol, seems to be mainly responsible of selective β-blockade, 6 whereas the l-form is the main effector of the endothelium-dependent vasorelaxant effect. 7,8 dl-Nebivolol exerts its vasodilatory action by activating endothelial nitric oxide synthase (eNOS) and by preventing eNOS uncoupling, thus enhancing NO production. 9 Endothelium-derived NO is a powerful inhibitor of platelet activation and an antithrombotic agent. 10,11 Besides endothelium, eNOS is present in other cells, including platelets, [12][13][14] and several in vitro and in vivo observations in animals and in humans suggest that platelet-derived NO plays a significant anti-inflammatory and antithrombotic role. [15][16][17][18][19] dl-Nebivolol was previously reported to inhibit ADP-and collagen-induced aggregation of human platelets in vitro, 20 an effect prevented by the previous exposure of platelets to a NOS inhibitor, such as L-NG-nitroarginine methyl ester, and enhanced by preincubation with l-arginine, the substrate of NOS, suggesting that the antiplatelet effect of dl-nebivolol is mediated by an enhanced release of NO from platelets. 4 © 2014 American Heart Association, Inc. Objective-dl-Nebivolol, a selective β1-adrenergic receptor antagonist, besides its hypotensive activity exerts vasodilatory and platelet inhibitory effects in vitro by a mechanism involving nitric oxide (NO). Our aim was to evaluate whether nebivolol exerts in vivo antithrombotic effects, to unravel the mechanism of this action and to clarify the relative roles of its 2 enantiomers: d-and l-nebivolol. Methods and Results-In wild-type mice, dl-nebivolol, l-nebivolol, and d-nebivolol, but not bisoprolol, reduced mortality consequent to platelet pulmonary thromboembolism induced by the intravenous injection of collagen plus epinephrine (−44%, −45%, −29%, respectively; P<0.05), whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were effective. dl-Nebivolol, l-and d-nebivolol reduced photochemical damage-induced femoral artery thrombosis in wild-type mice, whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were active. Moreover, dl-nebivolol and l-nebivolol increased plasma, urinary-, and platelet-derived nitrites and nitrates (NOx), NO degradation products, in ...

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Section: Discussionmentioning

confidence: 99%

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Momi

Caracchini

Falcinelli

et al. 2014

ATVB

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“…Although NO, by elevating intracellular cGMP, is known to inhibit platelet activation [18], it has been recently demonstrated that the major NO synthase (NOS) isoform expressed in platelets, the endothelial NOS (eNOS), may play a stimulatory role in low dose agonist-induced platelet activation and promote an in vivo thrombotic response in an injuryinduced arterial thrombosis model [15,17]. Such stimulatory role of eNOS would be dependent on NO-mediated sGC activation and elevation of cGMP, which in turn would promote the aggregation-dependent platelet secretion of granules contents [15,17]. Additional evidence indicates that low concentrations of NO promote a discrete platelet degranulation [23].…”

mentioning

confidence: 99%

“…Additional evidence indicates that low concentrations of NO promote a discrete platelet degranulation [23]. Given these latest findings, the current concept of NO signalling needs to be revised highlighting the plausible biphasic role of NO in platelet activation; at the low concentrations, produced by platelet eNOS, NO would promote platelet secretion and aggregation, while at higher concentrations NO would inhibit platelet activation [15,17]. 1 …”

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confidence: 99%

Altered nitric oxide/cGMP platelet signaling pathway in platelets from patients with acute coronary syndromes

et al. 2010

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Aim. To investigate whether the nitric oxide (NO)/cyclic GMP (cGMP) signalling pathway, in basal conditions and stimulated by sodium nitroprusside (SNP), may disclose abnormal patterns in platelets from patients with an acute coronary syndrome.Design. Platelet activation (sP-selectin), inflammation (TNF-α and erythrosedimentation rate), thrombotic state (fibrinogen) and plaque disruption (HsCRP) markers were assessed in ten patients with unstable angina (UA), 14 with acute myocardial infarction (AMI) and 14 age and sex macthed healthy subjects. Platelets homogenates western blot analysis were performed, in basal conditions and stimulated by SNP, to assess cGMP levels and the expression of the sGC isoforms. Upstream (Akt1 protein kinase α phosphorylation at Ser473 and eNOS phosphorylation) and downstream (vasodilatorstimulated phosphoprotein phosphorylation) signalling of the NO/cGMP pathway was tested in the three study groups. Results. Platelet activation, inflammation, thrombotic state and plaque disruption markers proved significantly higher in both the UA and AMI patients compared to healthy controls. Basal levels of cGMP (pmol/1010 platelets) were higher in platelets from UA (1097±111, p<0.0001) and AMI (1122±77, p<0.0001) patients compared to those from healthy controls (497±80). Similarly, serine phosphorylation in several proteins of the NO/cGMP signalling pathway (Akt1 protein kinase, NO synthase and VASP) was more represented in platelets from UA and AMI patients compared to controls. Following SNP stimulation AMI platelets disclosed a lack of cGMP increase and of VASP phosphorilation in comparison with healthy controls. Conclusion. The present study supports the hypothesis that low concentrations of endogenously synthesized NO and cGMP may promote platelet activation. The increased inflammatory state which often accompanies an acute coronary syndrome may be responsible of the platelet activation via the NO/cGMP pathway. Furthermore, platelets from AMI patients seem more resistant to SNP stimulation, exerted not only at the cGMP level but also at other signalling check-points.

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“…Moreover, data from an in vivo study reported that the NO/cGMP pathway may inhibit the signaling cascade of thromboxane A 2 receptor through phosphorylation by cGMP-dependent protein kinase (cGK), and through collagen-induced AA release by suppressing Ca 2þ -activated phospholipase A 2 activity [27]. Changes in the activity of platelet eNOS are responsible for abnormal platelet activation: recent evidence indicates a complex biphasic interaction between NO and platelet activation and aggregation; platelet-derived NO may stimulate platelets [28] through an initial transient stimulatory response, able to promote platelet aggregation, and a subsequent inhibitory response that limits the size of thrombi. Additional evidence indicates that low NO concentrations promote a platelet degranulation; on the contrary, high NO concentrations inhibit the exocytosis of dense granules [29].…”

Section: Discussionmentioning

confidence: 99%

Platelet aggregability is modulated by eNOS locus in non-type 2 diabetic patients with acute coronary syndrome☆

Fatini¹,

Sticchi²,

Bolli³

et al. 2011

Nutrition, Metabolism and Cardiovascular Diseases

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Background and aim: Platelet nitric oxide (NO) synthesis is compromised in patients with acute coronary syndrome (ACS), and platelet NO availability may be critically relevant in determining the extent of thrombosis in ACS patients. It has been demonstrated that an impaired responsiveness to the antiaggregatory effects of NO may affect platelet dysfunction in diabetic patients with ACS. Since NO availability may be genetically determined, we have investigated the role of endothelial nitric oxide synthase (eNOS) gene in influencing platelet aggregability in relation to the presence (n Z 247) or absence (n Z 883) of type 2 diabetes in ACS patients. Methods and results: We have genotyped 1130 consecutive high risk ACS patients on dual antiplatelet therapy, previously investigated in relation to platelet function. eNOS 4a allele frequency was significantly higher in diabetic vs. non-diabetic patients (p Z 0.02). In non-diabetic patients the eNOS 4a allele significantly modulated platelet aggregability in response to arachidonic acid (AA), but not to collagen and adenosine diphosphate (ADP) stimulus, after Bonferroni correction for multiple testing. After adjustment for age, gender, smoking habit, hypertension and ejection fraction 40%, the eNOS 4a allele remained significantly and independently associated with platelet aggregability in response to AA stimulus [b (SE) Z 0.17 (0.07), p Z 0.01]. When platelet aggregation values were considered according to the presence or absence of high residual platelet reactivity (RPR) eNOS 4a, but not À786C and 894T, allele was significantly associated with RPR by AA stimulus. The haplotype reconstruction analysis for eNOS gene showed that the À786C/894G/4a and À786C/894G/4b haplotypes significantly influenced platelet aggregation after AA stimulus. Conclusions: Our study indicates that eNOS 4a allele, may be a determinant of higher platelet aggregability and residual platelet reactivity in non-diabetic ACS patients. ª

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A Stimulatory Role for cGMP-Dependent Protein Kinase in Platelet Activation

Cited by 248 publications

References 44 publications

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Altered nitric oxide/cGMP platelet signaling pathway in platelets from patients with acute coronary syndromes

Platelet aggregability is modulated by eNOS locus in non-type 2 diabetic patients with acute coronary syndrome☆

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