A novel role of sesamol in inhibiting NF-κB-mediated signaling in platelet activation

Abstract

BackgroundPlatelet activation is relevant to a variety of coronary heart diseases. Our previous studies revealed that sesamol possesses potent antiplatelet activity through increasing cyclic AMP formation. Although platelets are anucleated cells, they also express the transcription factor, NF-κB, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of sesamol in NF-κB-mediated platelet function.MethodsPlatelet aggregation, Fura 2-AM fluorescence, and immunoblotting analysis were used in this study.ResultsNF-κB signaling events, including IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation, were markedly activated by collagen (1 μg/ml) in washed human platelets, and these signaling events were attenuated by sesamol (2.5~25 μM). Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate cyclase, respectively, strongly reversed the sesamol (25 μM)-mediated inhibitory effects of IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation stimulated by collagen. The protein kinase A (PKA) inhibitor, H89, also reversed sesamol-mediated inhibition of IκBα degradation. Moreover, BAY11-7082, an NF-κB inhibitor, abolished IκBα degradation, phospholipase C (PLC)γ2 phosphorylation, protein kinase C (PKC) activation, [Ca2+]i mobilization, and platelet aggregation stimulated by collagen. Preincubation of platelets with the inhibitors, SQ22536 and H89, both strongly reversed sesamol-mediated inhibition of platelet aggregation and [Ca2+]i mobilization.ConclusionsSesamol activates cAMP-PKA signaling, followed by inhibition of the NF-κB-PLC-PKC cascade, thereby leading to inhibition of [Ca2+]i mobilization and platelet aggregation. Because platelet activation is not only linked to hemostasis, but also has a relevant role in inflammation and metastasis, our data demonstrating that inhibition of NF-κB interferes with platelet function may have a great impact when these types of drugs are considered for the treatment of cancer and various inflammatory diseases.

Sesamol induces apoptosis in human platelets via reactive oxygen species-mediated mitochondrial damage

“…It also increases cAMP and cGMP levels, expression of endothelial nitric oxide synthase (eNOS) and NO release. In yet another study, Chang et al [12] have further advanced the investigation wherein they found that sesamol (2.5e 25 mM) stimulates cAMP-PKA signaling, subsequently inhibits NF- kB-PLC-PKC cascade, thereby leading to attenuation of Ca 2þ mobilization and inhibition of platelet aggregation. ADP-induced platelet aggregation occurs via the coordinated activation of two G proteinecoupled receptors, P2Y1 and P2Y12.…”

“…Besides, it is also used in the production of drugs for depression [11]. Recent studies have reported that sesamol in the concentration range 2.5e100 mM inhibits platelet aggregation by increasing the rate of cyclic AMP (cAMP) formation and attenuating the Nuclear Factor-kappa B (NF-kB) signaling events, thus depicting it to be an anti-thrombotic and cardioprotective compound [8,12]. However, the present study sought to demonstrate the effect of sesamol at higher concentrations on platelet functions, which is unknown hitherto.…”

Role of NF-κB Pathway on Platelet Activation

“…In fact, in the last sentence of the abstract, it is written "On the basis of these data, NF-κB is also identified as a new target to dampen unwanted platelet activation." The second article of Spinelli et al is just an editorial comment of the article published by Gambaryan et al 2 More important still, there is no mention of 7 other articles, [5][6][7][8][9][10][11] including a pioneer work from our group, 5 describing an opposite effect of NF-κB activation in platelets. In fact, using different strategies (including IkB kinase β knockout mice), these studies show that activation of NF-κB pathway promotes platelet activation.…”

Sesamol induces mitochondrial apoptosis pathway in HCT116 human colon cancer cells via pro-oxidant effect

“…1) has a wide range of biological actions, including: anti-mutagenesis [1]; antioxidant [2]; suppression of neuro-inflammation [3]; inhibition of atherosclerosis progression [4]; inhibition of NF-B in platelet aggregation [5,6]; and, reduction of plasma cholesterol and triacylglycerol levels [7].…”