The anandamide effect on NO/cGMP pathway in human platelets

Signorello, Maria Grazia; Giacobbe, Enrica; Passalacqua, Mario; Leoncini, Giuliana

doi:10.1002/jcb.23008

Cited by 19 publications

(24 citation statements)

References 54 publications

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“…We have shown that AEA stimulated eNOS phosphorylation in a dose‐dependent manner peaking at 10 μM (Fig. a) as previously published (Signorello et al, ). Several authors (Liu et al, ; Thors et al, ) reported that AMPKα can phosphorylate eNOS on ser1177, its positive regulatory site.…”

Section: Resultssupporting

confidence: 89%

Anandamide Induces Platelet Nitric Oxide Synthase through AMP‐Activated Protein Kinase

Signorello

Leoncini

2018

Lipids

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The objective of this study was to determine whether adenosine 5′ monophosphate (AMP)‐activated protein kinase (AMPK) is activated by anandamide (AEA) and is involved in endothelial nitric oxide synthase (eNOS) activation. We found that AEA stimulates and activates AMPKα through a Ca2+‐dependent/Calmodulin (CaM)‐dependent pathway as the specific inhibitor of the Ca2+/Calmodulin kinase kinase β (CaMKKβ) STO‐609 abolishes the AMPK phosphorylation/activation. The same inhibiting effect is shown in platelets pretreated with LY294002, an inhibitor of phosphatidylinositol 3 kinase (PI3K), or with MK2206, an inhibitor of protein kinase B (AKT), suggesting that AMPK is downstream of the PI3K/AKT pathway. Moreover, the AEA‐induced eNOS activation and the consequent nitric oxide (NO) and guanosine 3′‐5′ cyclic monophosphate (cGMP) increase are mediated by the CaMKKβ/AMPKα pathway as STO‐609 significantly inhibits these parameters. In contrast, liver kinase B1 (LKB1) seems to be very poorly involved. One crucial effect of NO and cGMP elevation is the activation of protein kinase G that can phosphorylate the vasodilator‐stimulated phosphoprotein (VASP). We have demonstrated that AEA stimulates VASP phosphorylation on both thr278 and ser239 that is strongly inhibited by STO‐609, LY294002, and MK2206. Finally, AMPK phosphorylation/activation and VASP phosphorylation are significantly reduced by SR141716, the specific inhibitor of type 1 cannabinoid receptor (CB1). SR144528, an antagonist of type 2 cannabinoid receptor (CB2), has a less‐potent effect, suggesting that the CB1 receptor is overall involved in the AEA effect. In conclusion, we show that the CaMKKβ/AMPKα pathway, downstream of the PI3K/AKT pathway, is activated by AEA in human platelets and leads to increase NO levels producing beneficial effects during ischemic conditions and contributing to extend platelet survival.

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Section: Resultssupporting

confidence: 89%

Anandamide Induces Platelet Nitric Oxide Synthase through AMP‐Activated Protein Kinase

Signorello

Leoncini

2018

Lipids

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“…To some extent these results were similar to the reports previously described [3,26], although the PLTs were incubated at 37°C in their studies. Previous studies also showed that millimole concentrations of ANA were able to activate human PLTs [6,16], but these levels are much higher than those in the blood [27].…”

Section: Discussionsupporting

confidence: 83%

“…So it has been speculated that the anti-apoptotic action of ANA can also occur in vivo [3]. Recently, Signorello et al reported that low concentrations of ANA contributed to extending PLT survival, through PI3K/Akt pathway activation, stimulating endothelial nitric oxide synthase activity and increasing nitric oxide (NO) levels in human PLTs [26]. Increasing the NO level in human PLTs could be one of many beneficial effects produced by ANA during ischemic conditions [29], as ANA produces vasodilatation in the arterial system [30].…”

Section: Discussionmentioning

confidence: 98%

In vitro properties of apheresis platelet during extended storage in plasma treated with anandamide

Zhuang¹,

Ren

et al. 2014

Transfusion and Apheresis Science

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“…dl-Nebivolol and l-nebivolol enhanced eNOS phosphorylation at serine1177, 1 of the phosphorylation sites involved in eNOS activation in platelets. [42][43][44] Tran Quang et al 45 showed that both d-and l-nebivolol stimulate vascular β3-adrenoceptors in rat aortae, and that this may be relevant to nebivolol-induced NO release. However, the presence of β3-AR has not been demonstrated in platelets that instead possess β1-and β2-AR.…”

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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The anandamide effect on NO/cGMP pathway in human platelets

Cited by 19 publications

References 54 publications

Anandamide Induces Platelet Nitric Oxide Synthase through AMP‐Activated Protein Kinase

Anandamide Induces Platelet Nitric Oxide Synthase through AMP‐Activated Protein Kinase

In vitro properties of apheresis platelet during extended storage in plasma treated with anandamide

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

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