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Key role of integrin ?(IIb)? (3) signaling to Syk kinase in tissue factor-induced thrombin generation.

ABSTRACT: The fibrin(ogen) receptor, integrin ?(IIb)?(3), has a well-established role in platelet spreading, aggregation and clot retraction. How ?(IIb)?(3) contributes to platelet-dependent coagulation is less well resolved. Here, we demonstrate that the potent suppressing effect of clinically used ?(IIb)?(3) blockers on tissue factor-induced thrombin generation is linked to diminished platelet Ca(2+) responses and phosphatidylserine (PS) exposure. The same blockers suppress these responses in platelets stimulated with collagen and thrombin receptor agonists, whereas added fibrinogen potentiates these responses. In platelets spreading on fibrinogen, outside-in ?(IIb)?(3) signaling similarly enhances thrombin-induced Ca(2+) rises and PS exposure. These responses are reduced in ?(IIb)?(3)-deficient platelets from patients with Glanzmann's thrombasthenia. Furthermore, the contribution of ?(IIb)?(3) to tissue factor-induced platelet Ca(2+) rises, PS exposure and thrombin generation in plasma are fully dependent on Syk kinase activity. Tyrosine phosphorylation analysis confirms a key role of Syk activation, which is largely but not exclusively dependent on ?(IIb)?(3) activation. It is concluded that the majority of tissue factor-induced procoagulant activity of platelets relies on Syk activation and ensuing Ca(2+) signal generation, and furthermore that a considerable part of Syk activation relies on ?(IIb)?(3) signaling. These results hence point to a novel role of Syk in integrin-dependent thrombin generation.

SUBMITTER: van der Meijden PE

PROVIDER: S-EPMC3445795 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Key role of integrin α(IIb)β (3) signaling to Syk kinase in tissue factor-induced thrombin generation.

van der Meijden Paola E J PE Feijge Marion A H MA Swieringa Frauke F Gilio Karen K Nergiz-Unal Reyhan R Hamulyák Karly K Heemskerk Johan W M JW

Cellular and molecular life sciences : CMLS 20120606 20

The fibrin(ogen) receptor, integrin α(IIb)β(3), has a well-established role in platelet spreading, aggregation and clot retraction. How α(IIb)β(3) contributes to platelet-dependent coagulation is less well resolved. Here, we demonstrate that the potent suppressing effect of clinically used α(IIb)β(3) blockers on tissue factor-induced thrombin generation is linked to diminished platelet Ca(2+) responses and phosphatidylserine (PS) exposure. The same blockers suppress these responses in platelets ...[more]

PMID: 22669259

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Project description:BackgroundBuyang Huanwu Decoction (BYHWD) is a traditional Chinese medicine to treat the syndrome of qi deficiency and blood stasis. Platelets play an important role in regulating thrombus and inflammation after ischemic injury, studies have shown that BYHWD regulate myocardial fibrosis and exert anti-inflammatory effects through IL-17 and TLR4 pathways, but the mechanism of platelet activation by BYHWD in stable coronary heart disease is still unknown. In the present study, model of left anterior descending coronary artery ligation was applied to investigate the mechanisms of BYHWD on modulating platelets hyperreactivity and heart function after fibrosis of ischemic myocardial infarction (MI).MethodsMyocardial infarction model was constructed by ligation of the left anterior descending coronary artery. The rats were randomly divided into five groups: sham, model, MI with aspirin (positive), MI with a low dosage of BYHWD (BYHWD-ld) and MI with a high dosage of BYHWD (BYHWD-hd) for 28 days.ResultsCoronary artery ligation prominently induced left ventricle dysfunction, increased cardiomyocyte fibrosis, which was accompanied by platelets with hyperreactivity, and high levels of inflammatory factors. BYHWD obviously reversed cardiac dysfunction and fibrosis, increased the thickness of the left ventricular wall, and inhibited aggregation ratio and CD62p expression. BYHWD restored the mitochondrial respiration of platelets after MI, concomitant with an increased telomere expression and decreased inflammation. According to the result of transcriptome sequencing, we found that 106 differentially expressed genes compared model with BYHWD treatment. Enrichment analysis screened out the Ras-related protein Rap-1 (Rap1) signaling pathway and platelet activation biological function. Quantitative real-time PCR and Western blotting were applied to found that BYHWD reduced the expression of Rap1/PI3K-Akt/Src-CDC42 genes and attenuated the overactivity of PI3 kinase/Rap1/integrin α(IIb)β(3) pathway.ConclusionBYHWD reduced inflammation and platelet activation via the PI3 kinase/Rap1/integrin α(IIb)β(3) pathway and improved heart function after MI.

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Dataset Information

Key role of integrin ?(IIb)? (3) signaling to Syk kinase in tissue factor-induced thrombin generation.

Publications

Key role of integrin α(IIb)β (3) signaling to Syk kinase in tissue factor-induced thrombin generation.

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