A noble function of BAY 11-7082: Inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations

Lee, Hyun-Sub; Kim, Sung Dae; Lee, Whi Min; Endale, Mehari; Kamruzzaman, S. M.; Oh, Won Zin; Cho, Jae Youl; Kim, Sang Keun; Cho, Hyun-Jeong; Park, Hwa-Jin; Rhee, Man Hee

doi:10.1016/j.ejphar.2009.11.005

Cited by 41 publications

(36 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with our data (Fig. 4), Spinelli et al (44) demonstrated expression of most NFB family members in platelets; however, in contrast to the two previous works (42)(43), reported significant platelet inhibitory effects already at low (0.5-5 M) concentrations of BAY 11-783 (44). However, to prove the specificity of BAY 11-783, the authors used a rather questionable method of introducing recombinant full-length proteins into platelets.…”

Section: Discussionsupporting

confidence: 47%

“…Expression of NFB (p65) and IB␣ proteins, and their activation by thrombin and other agonists have been shown in platelets (20). During preparation of this report for publication, three reports concerning NFB expression and function in platelets were published (42)(43)(44). In contrast to our data, authors of these works report that NFB plays a significant role in platelet activation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex

Gambaryan

Kobsar

Rukoyatkina

et al. 2010

Journal of Biological Chemistry

129

131

View full text Add to dashboard Cite

Protein kinase A (PKA) activation by cAMP phosphorylates multiple target proteins in numerous platelet inhibitory pathways that have a very important role in maintaining circulating platelets in a resting state. Here we show that in thrombin-and collagen-stimulated platelets, PKA is activated by cAMP-independent mechanisms involving dissociation of the catalytic subunit of PKA (PKAc) from an NFB-IB␣-PKAc complex. We demonstrate mRNA and protein expression for most of the NFB family members in platelets. From resting platelets, PKAc was co-immunoprecipitated with IB␣, and conversely, IB␣ was also co-immunoprecipitated with PKAc. This interaction was significantly reduced in thrombin-and collagen-stimulated platelets. Stimulation of platelets with thrombin-or collagen-activated IKK, at least partly by PI3 kinase-dependent pathways, leading to phosphorylation of IB␣, disruption of an IB␣-PKAc complex, and release of free, active PKAc, which phosphorylated VASP and other PKA substrates. IKK inhibitor inhibited thrombin-stimulated IkB␣ phosphorylation, PKAIkB␣ dissociation, and VASP phosphorylation, and potentiated integrin ␣IIb␤3 activation and the early phase of platelet aggregation. We conclude that thrombin and collagen not only cause platelet activation but also appear to fine-tune this response by initiating downstream NFB-dependent PKAc activation, as a novel feedback inhibitory signaling mechanism for preventing undesired platelet activation.Platelets are small anucleate cells derived from megakaryocytes in the bone marrow, in a process in which megakaryocyte cytoplasmic extensions into microvessels are sheared from their transendothelial stems by flowing blood (1-2). Platelets play a key role in the normal homeostatic process through their ability to rapidly adhere to activated and/or injured endothelium and subendothelial matrix proteins (platelet adhesion), and to other activated platelets (platelet aggregation). Many factors bind to specific platelet receptors and regulate signaling pathways, which promote or inhibit platelet adhesion, aggregation, and secretion. In vivo, circulating platelets are continually exposed to a variety of activating factors including collagen, fibrinogen, ADP, von Willebrand Factor (vWF), thrombin, and thromboxane (3-5), as well as inhibitory factors such as endothelial-derived nitric oxide (NO), prostacyclin (PG-I 2 ), and ADPase (3, 5-6). A strong equilibrium between the two opposing processes of platelet stimulation and inhibition is thought to be essential for normal platelet and vascular function. An impairment of this equilibrium will promote either thrombotic or bleeding disorders.In the initial steps of platelet activation, the platelet receptor glycoproteins (GP) 3 1b and GPVI interact with extracellular matrix (ECM) proteins, causing platelets to tether and roll on the injured endothelium or subendothelial ECM (5). Stimulation of these receptors triggers intracellular signaling cascades that activate integrin ␣IIb␤3 and induce the release of secondary mediators like A...

show abstract

Section: Discussionsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex

Gambaryan

Kobsar

Rukoyatkina

et al. 2010

Journal of Biological Chemistry

129

131

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: On "Platelets As Cellular Effectors Of Inflammation In Vascularmentioning

confidence: 99%

Role of NF-κB Pathway on Platelet Activation

Schattner

2013

Circulation Research

View full text Add to dashboard Cite

“…3A, Bay 11-7082 is able to reduce fibrinogen binding to glycoprotein GPIIb-IIIa (also named αIIbβ3 according to integrin nomenclature), thereby preventing thrombocyte aggregation. In addition, Bay 11-7082 inhibits thrombocyte activation and aggregation, and forces them to retain their granular contents, effects that are mediated by inhibition of JNK1 and ERK2 phosphorylation [25]. The fact that fibrinogen positively regulates NFκB activation and expression of inflammatory chemokines in endothelial cells [26] shows the multifunctional importance and applicability of such anti-inflammatory drugs as Bay 11-7082.…”

Section: Possible Role Of the Nfκb And The Glutathione Pathway In Blomentioning

confidence: 99%

“…Anti-thrombocyte agents, such as Bay 11-7082, inhibit this activation, thereby preventing thrombocyte aggregation [24]. B -Parthenolide is able to stimulate functional platelet production by inhibition of NFκB signaling [25] and to reduce thrombocyte aggregation [26]. C -Bay 11-7082 and parthenolide also inhibit the anti-oxidative defense and/or NFκB signaling in erythrocytes and concentration-dependently induce phosphatidylserine (PS) exposure on the erythrocyte surface.…”

Section: Possible Role Of the Nfκb And The Glutathione Pathway In Blomentioning

confidence: 99%

Roles of the NFκB and glutathione pathways in mature human erythrocytes

Ghashghaeinia¹,

Toulany²,

Saki³

et al. 2012

Cellular and Molecular Biology Letters

View full text Add to dashboard Cite

Abbreviations used: Ca 2+ -calcium; ERK2 -extracellular signal-regulated kinase 2; GPIIb/IIIa -glycoprotein IIb/IIIa; GSH -reduced glutathione; ICAM-1 -inter-cellular adhesion molecule; IFN-γ -interferon-γ; IκB-α -inhibitor of kappaB; IKK-α -IκB kinase-α; IL-6 -interleukin-6; IL-8 -interleukin-8; JNK1 -c-Jun N-terminal kinase 1; NFκB -nuclear factor κB; PS -phosphatidylserine; R -putative phosphatidylserine receptor Abstract: Anucleated erythrocytes were long considered as oxygen-transporting cells with limited regulatory functions. Components of different nuclear signaling pathways have not been investigated in those cells, yet. Surprisingly, we repeatedly found significant amounts of transcription factors in purified erythrocyte preparations, i.e. nuclear factor κB (NFκB), and major components of the canonical NFκB signaling pathway. To investigate the functional role of NFκB signaling, the effects of the preclinical compounds Bay 11-7082 and parthenolide on the survival of highly purified erythrocytes were investigated. Interestingly, both inhibitors of the NFκB pathway triggered erythrocyte programmed cell death as demonstrated by enhanced phospholipid scrambling Unauthenticated Download Date | 5/12/18 7:51 PM

show abstract

A noble function of BAY 11-7082: Inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations

Cited by 41 publications

References 38 publications

Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex

Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex

Role of NF-κB Pathway on Platelet Activation

Roles of the NFκB and glutathione pathways in mature human erythrocytes

Contact Info

Product

Resources

About