Involvement of Rac in thromboxane A2-induced human platelet activation: Regulation of sCD40 ligand release and PDGF-AB secretion

Kageyama, Yasunari; Doi, Tomoaki; Matsushima‐Nishiwaki, Rie; Iida, Yuko; Akamatsu, Shigeru; Kondo, Akira; Kuroyanagi, Gen; Yamamoto, Naohiro; Mizutani, Jun; Otsuka, Takanobu; Tokuda, Harukuni; Iida, Hiroki; Kozawa, Osamu; Ogura, Shinji

doi:10.3892/mmr.2014.2143

Cited by 6 publications

(8 citation statements)

References 22 publications

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“…HSP27 is a substrate for AKT, and it regulates actin dynamics and degranulation. This confirms the earlier finding that MAPK activation stimulates platelet degranulation and TxA2 synthesis, which may in turn activate platelets via the TP receptor [ 113 ]. After degranulation, soluble factors (ADP, ATP, TxA2, Ca 2+ and thrombin) are released and may act quickly to amplify autocrine activation of platelets as well as the activation of surrounding platelets ( Figure 4 ) [ 88 ].…”

Section: Platelets Cd40l and Molecular Signalingsupporting

confidence: 92%

The Signaling Role of CD40 Ligand in Platelet Biology and in Platelet Component Transfusion

Aloui

Prigent

Sut

et al. 2014

IJMS

144

116

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The CD40 ligand (CD40L) is a transmembrane molecule of crucial interest in cell signaling in innate and adaptive immunity. It is expressed by a variety of cells, but mainly by activated T-lymphocytes and platelets. CD40L may be cleaved into a soluble form (sCD40L) that has a cytokine-like activity. Both forms bind to several receptors, including CD40. This interaction is necessary for the antigen specific immune response. Furthermore, CD40L and sCD40L are involved in inflammation and a panoply of immune related and vascular pathologies. Soluble CD40L is primarily produced by platelets after activation, degranulation and cleavage, which may present a problem for transfusion. Soluble CD40L is involved in adverse transfusion events including transfusion related acute lung injury (TRALI). Although platelet storage designed for transfusion occurs in sterile conditions, platelets are activated and release sCD40L without known agonists. Recently, proteomic studies identified signaling pathways activated in platelet concentrates. Soluble CD40L is a good candidate for platelet activation in an auto-amplification loop. In this review, we describe the immunomodulatory role of CD40L in physiological and pathological conditions. We will focus on the main signaling pathways activated by CD40L after binding to its different receptors.

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Section: Platelets Cd40l and Molecular Signalingsupporting

confidence: 92%

The Signaling Role of CD40 Ligand in Platelet Biology and in Platelet Component Transfusion

Aloui

Prigent

Sut

et al. 2014

IJMS

144

116

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“…12 In regard to platelet aggregation, we previously reported that both Rho and Rac are involved in human platelet activation, including PDGF-AB secretion induced by thromboxane A2. 13,14 We also reported that collagen-induced human platelet activation is regulated by Rac. 15 However, the exact mechanism behind the effects of TPO and collagen interactions on platelet activation has not yet been elucidated.…”

Section: Introductionmentioning

confidence: 86%

“…Rho and the downstream effector Rho‐associated kinase (Rho‐kinase) are currently established to play crucial roles in various cellular functions 12 . In regard to platelet aggregation, we previously reported that both Rho and Rac are involved in human platelet activation, including PDGF‐AB secretion induced by thromboxane A2 13,14 . We also reported that collagen‐induced human platelet activation is regulated by Rac 15 .…”

Section: Introductionmentioning

confidence: 99%

Thrombopoietin and collagen in low doses cooperatively induce human platelet activation

Doi

Hori

Onuma

et al. 2022

Acute Medicine & Surgery

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Aim In acute medicine, we occasionally treat life‐threatening conditions such as sepsis and trauma, which cause severe thrombocytopenia. Serum thrombopoietin levels have been reported to increase under the condition of thrombocytopenia related to severity. Collagen is a crucial activator of platelets, and Rho family members, such as Rho/Rho‐kinase and Rac, play roles as active molecules involved in the intracellular signaling pathways in platelet activation. The present study aimed to elucidate the effects of thrombopoietin (TPO) on subthreshold low‐dose collagen‐stimulated human platelets in terms of Rho/Rho‐kinase and Rac. Methods Platelet‐rich plasma donated from healthy volunteers was stimulated by the subthreshold low‐dose of collagen after pretreatment with TPO and/or NSC23766, an inhibitor of the Rac‐guanine nucleotide exchange factor interaction, or Y27632, an inhibitor of Rho‐kinase. Platelet aggregation was measured using an aggregometer based on laser‐scattering methods. Proteins involved in intracellular signaling were analyzed using western blotting, and the secretion of platelet‐derived growth factor‐AB from activated platelets was determined using an enzyme‐linked immunosorbent assay. Results Under the existence of TPO, the low dose of collagen remarkably elicited the aggregation and platelet‐derived growth factor‐AB secretion of platelets, which were suppressed by NSC23766 and Y27632. The combination of TPO and collagen considerably induced a transient increase of guanosine triphosphate (GTP)‐binding Rac and GTP‐binding Rho followed by an increase of phosphorylated cofilin, a Rho‐kinase substrate. Conclusion These results strongly suggest that TPO and collagen in low doses cooperatively potentiate human platelet activation through both Rac and Rho/Rho‐kinase mediated pathways.

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“…Regarding Rac in human platelets, it has recently been reported that Rac is implicated in platelet aggregation, the activation of α IIb β 3 or phospholipase C, and granule secretion [10][11][12][13]. In our previous report [14], we showed that Rac acts as a positive regulator of the release of soluble CD40 ligand (sCD40L) and the secretion of platelet-derived growth factor-AB (PDGF-AB) induced by TXA 2 from human platelets. Regarding the relationship between PARs and Rac in human platelets, it has been reported that Rac is activated by PAR stimulation [15,16].…”

Section: Introductionmentioning

confidence: 91%

Rac Regulates the TRAP-Induced Release of Phosphorylated-HSP27 from Human Platelets via p38 MAP Kinase but Not JNK

Uematsu

Enomoto

Onuma

et al. 2018

Cell Physiol Biochem

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Background/Aims: Thrombin induces the activation of human platelets through protease-activated receptor (PAR) 1 and PAR4, and Rac, a member of the Rho family of small GTPases, is implicated in PAR activation. We previously reported that phosphorylated-heat shock protein 27 (HSP27) is released from the thrombin receptor-activating peptide (TRAP)-stimulated platelets of diabetic patients. In the present study, we investigated the role of Rac in the TRAP-elicited release of phosphorylated-HSP27 from human platelets. Methods: Platelet aggregation was measured using an aggregometer with laser scattering. Protein phosphorylation was analyzed by Western blotting. The levels of phosphorylated-HSP27 and platelet-derived growth factor-AB (PDGF-AB) were measured by enzyme-linked immunosorbent assays. Results: NSC23766, an inhibitor of Rac-guanine nucleotide exchange factor interaction, suppressed the TRAP-elicited release of phosphorylated-HSP27 as well as platelet aggregation. The TRAP-induced phosphorylation of HSP27, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) was attenuated by NSC23766. SB203580, a p38 MAPK inhibitor, but not SP600125, a JNK inhibitor, suppressed the release of phosphorylated-HSP27 in addition to HSP27 phosphorylation. On the other hand, both SB203580 and SP600125 reduced the TRAP-stimulated secretion of PDGF-AB. Conclusion: Our results strongly suggest that Rac acts as a positive regulator of the PAR-elicited release of phosphorylated-HSP27 from human platelets via p38 MAPK but not JNK.

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Involvement of Rac in thromboxane A2-induced human platelet activation: Regulation of sCD40 ligand release and PDGF-AB secretion

Cited by 6 publications

References 22 publications

The Signaling Role of CD40 Ligand in Platelet Biology and in Platelet Component Transfusion

The Signaling Role of CD40 Ligand in Platelet Biology and in Platelet Component Transfusion

Thrombopoietin and collagen in low doses cooperatively induce human platelet activation

Rac Regulates the TRAP-Induced Release of Phosphorylated-HSP27 from Human Platelets via p38 MAP Kinase but Not JNK

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