Involvement of the Mitogen-activated Protein Kinase c-Jun NH2-terminal Kinase 1 in Thrombus Formation

Kauskot, Alexandre; Adam, Frédéric; Mazharian, Alexandra; Ajzenberg, Nadine; Berrou, Eliane; Bonnefoy, Arnaud; Rosa, Jean‐Philippe; Hoylaerts, Marc; Bryckaert, Marijke

doi:10.1074/jbc.m701596200

Cited by 39 publications

(47 citation statements)

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“…However, in the absence of studies of radiation chimeras, we cannot rule out the contribution of a vasculature defect to the phenotype. However, this is unlikely because our previous in vivo findings based on the use of JNK inhibitors 21 and the markedly lower levels of thrombus formation by isolated JNK1 Ϫ/Ϫ platelets in our in vitro blood flow studies strongly suggest a significant and direct effect of JNK1 on platelet function.…”

Section: Discussionmentioning

confidence: 64%

“…21 Here, we clearly identify JNK1 as one of the JNK isoforms involved in hemostasis and thrombosis. Occlusion times for the arterioles of JNK1 Ϫ/Ϫ and WT mice differed to a greater extent in this study (4.3 times greater in JNK1 Ϫ/Ϫ mice) than in our previous study, based on the use of a pan-JNK inhibitor in WT mice (1.9 times greater with the inhibitor).…”

Section: Discussionmentioning

confidence: 99%

“…12 Our previous studies with inhibitors of all JNK isoforms (JNK1, JNK2, and JNK3) suggested a role for JNKs in platelet adhesion and thrombus formation. 21 Chen et al observed the CD36-dependent activation of JNK by oxidized low-density lipoprotein in platelets. 14 Thus, although some knowledge has been gained in the role of JNK MAP kinases in platelet activation, the underlying mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

“…[15][16][17][18] In contrast, little is known about either the activation or the role of JNK1 and JNK2 in platelets. 19 In human platelets, the JNK1 isoform is activated by thrombin, 12 VWF, 20 and collagen, 21 and JNK1 activation by thrombin is down-regulated by ␣IIb␤3. 12 Our previous studies with inhibitors of all JNK isoforms (JNK1, JNK2, and JNK3) suggested a role for JNKs in platelet adhesion and thrombus formation.…”

Section: Introductionmentioning

confidence: 99%

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Platelet JNK1 is involved in secretion and thrombus formation

Adam

Kauskot

Nurden

et al. 2010

Blood

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105

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The role of c-Jun NH 2 -terminal kinase 1 (JNK1) in hemostasis and thrombosis remains unclear. We show here, with JNK1-deficient (JNK1 ؊/؊ ) mice, that JNK1 plays an important role in platelet biology and thrombus formation. In tail-bleeding assays, JNK1 ؊/؊ mice exhibited longer bleeding times than wild-type mice (396 ؎ 39 seconds vs 245 ؎ 32 seconds). We also carried out in vitro whole-blood perfusion assays on a collagen matrix under arterial shear conditions. Thrombus formation was significantly reduced for JNK1 ؊/؊ platelets (51%). In an in vivo model of thrombosis induced by photochemical injury to cecum vessels, occlusion times were 4.3 times longer in JNK1 ؊/؊ arterioles than in wild-type arterioles. Moreover, in vitro studies carried out in platelet aggregation conditions demonstrated that, at low doses of agonists, platelet secretion was impaired in JNK1 ؊/؊ platelets, leading to altered integrin ␣IIb␤3 activation and reduced platelet aggregation, via a mechanism involving protein kinase C. JNK1 thus appears to be essential for platelet secretion in vitro, consistent with its role in thrombus growth in vivo. Finally, we showed that ERK2 and another isoform of JNK affect platelet aggregation through 2 pathways, one dependent and another independent of JNK1.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Platelet JNK1 is involved in secretion and thrombus formation

Adam

Kauskot

Nurden

et al. 2010

Blood

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105

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“…50 In addition to ERK, the MAPK family members c-Jun N-terminal kinase 1 and p38 are present in platelets. [51][52][53] Whereas p38 signaling has been linked to cPLA 2 phosphorylation in platelets stimulated by various agonists, 54,55 no such role has been described for c-Jun N-terminal kinase 1. In addition to MAPK signaling, Shattil and colleagues recently demonstrated that integrin outside-in signaling could directly affect the enzymatic activity of a pool of cPLA 2 ␣ bound to the integrin.…”

Section: Caldag-gefi In Platelet Calciummentioning

confidence: 99%

CalDAG-GEFI is at the nexus of calcium-dependent platelet activation

Stefanini

Roden

Bergmeier

2009

Blood

135

147

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The importance of the second messengers calcium (Ca 2؉ ) and diacylglycerol (DAG) in platelet signal transduction was established more than 30 years ago. Whereas protein kinase C (PKC) family members were discovered as the targets of DAG, little is known about the molecular identity of the main Ca 2؉ sensor(s). We here identify Ca 2؉ and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) as a critical molecule in Ca 2؉ -dependent platelet activation. CalDAG-GEFI, through activation of the small GTPase Rap1, directly triggers integrin activation and extracellular signalregulated kinase-dependent thromboxane A 2 (TxA 2 ) release. CalDAG-GEFIdependent TxA 2 generation provides crucial feedback for PKC activation and granule release, particularly at threshold agonist concentrations. PKC/P2Y12 signaling in turn mediates a second wave of Rap1 activation, necessary for sustained platelet activation and thrombus stabilization. Our results lead to a revised model for platelet activation that establishes one molecule, CalDAG-GEFI, at the nexus of Ca 2؉ -induced integrin activation, TxA 2 generation, and granule release. The preferential activation of CalDAG-GEFI over PKC downstream of phospholipase C activation, and the different kinetics of CalDAG-GEFI-and PKC/P2Y12-mediated Rap1 activation demonstrate an unexpected complexity to the platelet activation process, and they challenge the current model that DAG/PKC-dependent signaling events are crucial for the initiation of platelet adhesion. IntroductionPlatelet thrombus formation at sites of vascular injury is a complex and dynamic process that occurs in several phases. 1,2 Platelet preactivation and tethering (transient adhesion) are mediated by the interaction of glycoprotein (GP) lb␣ with matrix-bound von Willebrand factor, particularly in conditions of high shear. Platelet activation and firm adhesion are then triggered by collagen exposed in the vessel wall and/or locally generated thrombin. Sustained integrin activation and the formation of stable thrombi further depend on persistent costimulatory signaling provided by the second wave agonists, thromboxane A 2 (TxA 2 ) and adenosine 5Ј-diphosphate (ADP), which are released from activated platelets. [3][4][5] The central biochemical event in platelet aggregation is the agonist-induced inside-out activation of ␣ IIb ␤ 3 integrin. Most platelet agonists initiate intracellular signaling through the activation of phospholipase C (PLC), followed by the generation of the second messengers calcium (Ca 2ϩ ) and diacylgycerol (DAG). DAG is critical for protein kinase C (PKC) activation, a key event in platelet granule release and integrin activation. Platelets express at least 6 PKC isoforms, which have activating as well as inhibitory roles in platelet activation. [6][7][8][9][10] Early studies with calcium ionophores established a role of Ca 2ϩ in integrin activation, TxA 2 generation, and granule release. 11-13 Initially, Ca 2ϩ -binding classical isoforms of PKC were suggested as the cell's main signal integ...

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Antiplatelet Activity of Phellinus baummii Methanol Extract is Mediated by Cyclic AMP Elevation and Inhibition of Collagen‐activated Integrin‐α_IIbβ₃ and MAP Kinase

Kamruzzaman

Endale

et al. 2011

Phytotherapy Research

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Phellinus baumii is a mushroom that has been used as folk medicine against various diseases and is reported to have antidiabetic, anticancer, antioxidant, antiinflammatory and antihypertensive activities. However, information on the effects of P. baumii extract in platelet function is limited. Therefore, the aim of this study was to examine the impact of a P. baumii methanol extract (PBME) on platelet activation and to investigate the mechanism behind its antiplatelet activity. PBME effects on agonist-induced platelet aggregation, granule secretion, [Ca²⁺](i) mobilization, α(IIb) β₃ activation, cyclic AMP release and mitogen-activated protein kinase (MAPK) phosphorylations were studied using rat platelets. PBME dose-dependently inhibited collagen, thrombin and ADP-induced platelet aggregation with an IC₅₀ of 51.0 ± 2.4, 54.0 ± 2.1 and 53.0 ± 4.3 μg/mL, respectively. Likewise, thrombin-induced [Ca²⁺](i) and collagen-activated ATP secretions were suppressed in PBME treated platelets. Aggregation and ATP secretion were also markedly attenuated by PBME alone or in combination with PP2 (Src inhibitor) and U-73122 (PLC inhibitor) in collagen-stimulated platelets. Besides, PBME treatment elevated basal cyclic AMP levels and inhibited collagen-induced integrin-α(IIb) β₃ activation. Moreover, PBME attenuated extracellular-signal-regulated protein kinase 2 (ERK2) and c-Jun N-terminal kinase 1 (JNK1) phosphorylations. Further PD98059 (ERK inhibitor) and SP60025 (JNK inhibitor) reduced collagen-induced platelet aggregation and ATP secretion. In conclusion, the observed PBME antiplatelet activity may be mediated by activation of cyclic AMP and inhibition of ERK2 and JNK1 phosphorylations. Finally, these data suggest that PBME may have therapeutic potential for the treatment of cardiovascular diseases that involve aberrant platelet function.

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Involvement of the Mitogen-activated Protein Kinase c-Jun NH2-terminal Kinase 1 in Thrombus Formation

Cited by 39 publications

References 50 publications

Platelet JNK1 is involved in secretion and thrombus formation

Platelet JNK1 is involved in secretion and thrombus formation

CalDAG-GEFI is at the nexus of calcium-dependent platelet activation

Antiplatelet Activity of Phellinus baummii Methanol Extract is Mediated by Cyclic AMP Elevation and Inhibition of Collagen‐activated Integrin‐α_IIbβ₃ and MAP Kinase

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Involvement of the Mitogen-activated Protein Kinase c-Jun NH2-terminal Kinase 1 in Thrombus Formation

Cited by 39 publications

References 50 publications

Platelet JNK1 is involved in secretion and thrombus formation

Platelet JNK1 is involved in secretion and thrombus formation

CalDAG-GEFI is at the nexus of calcium-dependent platelet activation

Antiplatelet Activity of Phellinus baummii Methanol Extract is Mediated by Cyclic AMP Elevation and Inhibition of Collagen‐activated Integrin‐αIIbβ3 and MAP Kinase

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Antiplatelet Activity of Phellinus baummii Methanol Extract is Mediated by Cyclic AMP Elevation and Inhibition of Collagen‐activated Integrin‐α_IIbβ₃ and MAP Kinase