Src family kinase–mediated and Erk-mediated thromboxane A2 generation are essential for VWF/GPIb-induced fibrinogen receptor activation in human platelets

Garcia, Analia; Quinton, Todd M.; Dorsam, Robert T.; Kunapuli, Satya P.

doi:10.1182/blood-2005-05-1933

Cited by 106 publications

(118 citation statements)

References 27 publications

(36 reference statements)

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“…It was previously shown that phosphorylation of Akt and/or ERK plays a critical role in platelet function,60, 61, 62 and supports thrombus formation 63, 64. Thus, we examined whether e‐cigarettes exert any effect on these 2 markers of platelet activation.…”

Section: Resultsmentioning

confidence: 95%

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

Qasim

Karim

Silva‐Espinoza

et al. 2018

JAHA

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BackgroundCardiovascular disease is the main cause of death in the United States, with smoking being the primary preventable cause of premature death, and thrombosis being the main mechanism of cardiovascular mortality in smokers. Due to the perception that electronic/e‐cigarettes are “safer/less harmful” than conventional cigarettes, their usage—among a variety of ages—has increased tremendously during the past decade. Notably, there are limited studies regarding the negative effects of e‐cigarettes on the cardiovascular system, which is also the subject of significant debate.Methods and ResultsWe employed a passive e‐VapeTM vapor inhalation system and developed an in vivo whole‐body e‐cigarette mouse exposure protocol that mimics real‐life human exposure scenarios/conditions and investigated the effects of e‐cigarettes and clean air on platelet function and thrombogenesis. Our results show that platelets from e‐cigarette–exposed mice are hyperactive, with enhanced aggregation, dense and α granule secretion, activation of the αIIbβ3 integrin, phosphatidylserine expression, and Akt and ERK activation, when compared with clean air–exposed platelets. E‐cigarette–exposed platelets were also found to be resistant to inhibition by prostacyclin, relative to clean air. Furthermore, the e‐cigarette–exposed mice exhibited a shortened thrombosis occlusion and bleeding times.ConclusionsTaken together, our data demonstrate for the first time that e‐cigarettes alter physiological hemostasis and increase the risk of thrombogenic events. This is attributable, at least in part, to the hyperactive state of platelets. Thus, the negative health consequences of e‐cigarette exposure should not be underestimated and warrant further investigation.

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Section: Resultsmentioning

confidence: 95%

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

Qasim

Karim

Silva‐Espinoza

et al. 2018

JAHA

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“…Others have shown that GPIb signaling activates ERK1/2. 25,43 Our data demonstrate that bt/VWF-induced agglutination also activates ERK1/2 and that Btk is required for activation of ERK1/2 ( Figure 4C). …”

Section: Btk Is Upstream Of Akt Pkc and Erk1/2mentioning

confidence: 82%

“…This aspect of GPIb signaling is important because agglutination-elicited TxA2 production is required for ␣IIb␤3 activation in this GPIb-dependent signaling system. 5,25 The results of this investigation demonstrate that Btk is essential for both bt/VWF-induced TxA2 production and stable GPIb-dependent thrombus formation in FeCl 3 -treated, mouse carotid arteries, as well as clarify, at least in part, the role of Btk in this signaling system.…”

Section: Introductionmentioning

confidence: 90%

“…The GPIb␣-mediated agglutination phase of the biphasic response initiates a signaling cascade that elicits TxA2 production that is prerequisite for activation of ␣IIb␤3. 5,25 The agglutination-elicited signaling that causes agglutination-dependent TxA2 production is initiated by Lyn, enhanced by Src, and propagated through Syk, SLP-76, PI3K, PLC␥2, and PKC. 14 The work presented here extends our understanding of this agglutination-elicited signaling by demonstrating that the resultant TxA2 production requires Btk.…”

Section: Discussionmentioning

confidence: 99%

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Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo

Liu

Fitzgerald

Berndt

et al. 2006

Blood

129

113

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“…2,[4][5][6] Recently, new mechanisms for agonist-induced platelet activation and secretion were proposed to involve sequential activation of cGMP-dependent protein kinase (PKG)/p38/integrin or Akt/ eNOS/sGC/cGMP/PKG secretion, respectively, 7-9 whereas others indicate an essential role of Src/ERK-mediated TxA 2 generation for fibrinogen receptor activation in human platelets. 10 We 11,12 and others 10,13 were unable to reproduce the reported ERK activation by PKG. However, both the upstream mechanisms of p38 activation, and their downstream effects, are presently controversial and unclear.…”

Section: Introductionmentioning

confidence: 90%

Thrombin stimulation of p38 MAP kinase in human platelets is mediated by ADP and thromboxane A2 and inhibited by cGMP/cGMP-dependent protein kinase

Begonja

Geiger

Rukoyatkina

et al. 2006

Blood

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p38 MAP kinase in human platelets is activated by platelet agonists including thrombin, thromboxane A 2 (TxA 2 ), ADP, and others. However, both upstream mechanisms of p38 MAP kinase activation, and their downstream sequelae, are presently controversial and essentially unclear. Certain studies report sequential activation of cGMP-dependent protein kinase (PKG) and p38/ERK pathways by platelet agonists, leading to integrin activation and secretion, whereas others establish an essential role of Src/ERKmediated TxA 2 generation for fibrinogen receptor activation in human platelets. Here, we show that ADP secreted from platelet-dense granules, and subsequent activation of P2Y 12 receptors, as well as TxA 2 release are important upstream mediators of p38 MAP kinase activation by thrombin. However, p38 MAP kinase activation did not significantly contribute to calcium mobilization, P-selectin expression, ␣IIb␤3 integrin activation, and aggregation of human platelets in response to thrombin. Finally IntroductionIn vivo, circulating platelets are continually exposed to both adhesive and/or activating factors (fibrinogen, ADP, von Willebrand factor [VWF], thrombin, TxA 2 , etc), as well as inhibitory factors such as endothelium-derived nitric oxide (NO), prostacyclin (PG-I 2 ), and ADPase. 1 Most of these activating and inhibitory molecules bind to specific platelet receptors and stimulate signaling pathways that promote or inhibit platelet adhesion, aggregation, and secretion. A central role among platelet-activating factors is played by ADP, which induces multiple platelet responses and potentiates platelet aggregation caused by other agonists. 2,3 ADP is released from platelet-dense granules upon activation by agonists such as thrombin and collagen, and binds to purinergic receptors (P2Y 1 , P2Y 12 , P2X 1 ) to reinforce platelet aggregation and thrombus formation. 2,[4][5][6] Recently, new mechanisms for agonist-induced platelet activation and secretion were proposed to involve sequential activation of cGMP-dependent protein kinase (PKG)/p38/integrin or Akt/ eNOS/sGC/cGMP/PKG secretion, respectively, 7-9 whereas others indicate an essential role of Src/ERK-mediated TxA 2 generation for fibrinogen receptor activation in human platelets. 10 We 11,12 and others 10,13 were unable to reproduce the reported ERK activation by PKG. However, both the upstream mechanisms of p38 activation, and their downstream effects, are presently controversial and unclear. Here, we show that ADP secreted from platelet-dense granules, and subsequent activation of P2Y 12 receptors, as well as TxA 2 secretion are important mediators upstream of thrombin-evoked p38 activation. Furthermore, PKG activation does not stimulate, but rather inhibits, thrombin-evoked p38 activation, which alone has no significant effect on platelet stimulation/aggregation. Materials and methodsAnalysis of P-selectin expression, ␣IIb␤3 activation, aggregation, and intracellular calcium measurement Platelets were isolated from whole blood obtained from healthy volunteer...

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Src family kinase–mediated and Erk-mediated thromboxane A2 generation are essential for VWF/GPIb-induced fibrinogen receptor activation in human platelets

Cited by 106 publications

References 27 publications

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo

Thrombin stimulation of p38 MAP kinase in human platelets is mediated by ADP and thromboxane A2 and inhibited by cGMP/cGMP-dependent protein kinase

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