Inflammatory Cytokine TSLP Stimulates Platelet Secretion and Potentiates Platelet Aggregation via a TSLPR-Dependent PI3K/Akt Signaling Pathway

Dong, Jiyang; Lin, Jing; Wang, Boyuan; He, Shan; Wu, Chun; Kushwaha, Kishan Kumar; Mohabeer, Nilesh; Su, Yousu; Fang, Hongcheng; Huang, Kai; Li, Dazhu

doi:10.1159/000369684

Cited by 25 publications

(21 citation statements)

References 45 publications

(61 reference statements)

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“…Thrombin-mediated platelet activation is associated with rapid depolymerization of F-actin prior to the release of Ca 2+ from intracellular stores and the induction of Ca 2+ entry [24]. Platelet activation and migration as well as thrombus formation are related to PI3K/Akt signaling [25][26][27]. We and others have reported that PI3K-mediated stimulation of platelets through the TRPC6 channel is involved in platelet activation in diabetic patients [2,28].…”

Section: Discussionmentioning

confidence: 98%

Enhanced Store-Operated Calcium Entry in Platelets is Associated with Peripheral Artery Disease in Type 2 Diabetes

Xia

Wang

et al. 2015

Cell Physiol Biochem

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Background/Aims: Platelet dysfunction plays an important role in thrombosis in diabetes with peripheral artery disease (PAD). Store-operated calcium entry (SOCE) and stromal interaction molecule 1 (STIM1) regulate platelet activity by modulating calcium influx. We hypothesized that enhanced SOCE in platelets is associated with diabetes with PAD. Methods: We studied the activity of platelets from healthy participants and from type 2 diabetic patients. Platelet calcium influx and protein expression of STIM1 and sarcoendoplasmic reticulum Ca²⁺-ATPase 3 (SERCA3) were investigated. Results: Compared with platelets from diabetic patients without PAD, platelets from diabetic patients with PAD exhibited significantly increased SOCE . Menthol administration completely inhibited calcium influx in platelets from diabetic patients without PAD, but this effect was blunted in those from diabetic patients with PAD. Furthermore, the increase in SOCE was correlated with the ankle brachial index (ABI) in diabetic patients. High glucose significantly up-regulated STIM1 and SERCA3 protein expression and induced the phosphorylation of phospholipase C (PLC) in platelets from healthy participants. This effect was attenuated in the presence of menthol or U73122, an inhibitor of PLC. Similarly, significant increases in STIM1 and SERCA3 protein expression were found in platelets from diabetic patients compared to those from healthy participants. Conclusion: Platelets from diabetic patients with PAD exhibited enhanced Store-operated calcium influx, which was associated with elevated STIM1/SERCA3 expression via a PLC-dependent pathway and was inhibited by menthol.

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Section: Discussionmentioning

confidence: 98%

Enhanced Store-Operated Calcium Entry in Platelets is Associated with Peripheral Artery Disease in Type 2 Diabetes

Xia

Wang

et al. 2015

Cell Physiol Biochem

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“…Chorein has previously been shown to interact with PI3K [1,2], which is known to participate in the regulation of degranulation in a wide variety of cells [32,33,34,35,36,37,38,39,40]. Possibly, chorein similarly modifies degranulation of those cells.…”

Section: Discussionmentioning

confidence: 99%

Chorein Sensitive Dopamine Release from Pheochromocytoma (PC12) Cells

Honisch¹,

Fehrenbacher

Lebedeva

et al. 2015

Neurosignals

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Background: Chorein, a protein supporting activation of phosphoinositide 3 kinase (PI3K), participates in the regulation of actin polymerization and cell survival. A loss of function mutation of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) leads to chorea-acanthocytosis (ChAc), a neurodegenerative disorder with simultaneous erythrocyte akanthocytosis. In blood platelets chorein deficiency has been shown to compromise expression of vesicle-associated membrane protein 8 (VAMP8) and thus degranulation. The present study explored whether chorein is similarly involved in VAMP8 expression and dopamine release of pheochromocytoma (PC12) cells. Methods: Chorein was down-regulated by silencing in PC12 cells. Transmission electron microscopy was employed to quantify the number of vesicles, RT-PCR to determine transcript levels, Western blotting to quantify protein expression and ELISA to determine dopamine release. Results: Chorein silencing significantly reduced the number of vesicles, VAMP8 transcript levels and VAMP8 protein abundance. Increase of extracellular K⁺ from 5 mM to 40 mM resulted in marked stimulation of dopamine release, an effect significantly blunted by chorein silencing. Conclusions: Chorein deficiency down-regulates VAMP8 expression, vesicle numbers and dopamine release in pheochromocytoma cells.

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“…Fluorophore-labeled antibodies were utilized for the detection of P-selectin expression (Wug.E9-FITC) [33] and the active form of α IIb β 3 integrin (JON/A-PE) [34]. Washed mouse platelets (1x10 6 ) were suspended in modified Tyrode buffer (pH 7.4) containing 1 mM CaCl 2 and antibodies (1: 10 dilution) and subsequently subjected to the respective treatments and for the indicated time periods at room temperature (RT).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Collagen Related Peptide Induced Platelet Activation and Apoptosis by Ceritinib

Cao

Umbach

Bissinger

et al. 2018

Cell Physiol Biochem

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Background/Aims: The anaplastic lymphoma (tyrosine) kinase (ALK) inhibitor ceritinib triggers apoptosis of tumor cells and eryptosis of erythrocytes. Blood platelets may similarly enter a state resembling apoptosis, which could be triggered by activation with collagen related peptide (CRP). CRP-induced platelet apoptosis is characterized by cell membrane scrambling with phosphatidylserine exposure to the platelet surface and cell shrinkage, preceded by externalization of Ca²⁺ channel Orai1, increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i), formation of reactive oxygen species (ROS), and caspase activation. The present study explored whether ceritinib triggers platelet apoptosis and/or modifies the CRP induced apoptosis. Methods: Platelets isolated from wild-type mice were exposed for 30 minutes to ceritinib (1.5 µg/ml) without or with 2.5 – 15 min pretreatment with CRP (2 µg/ml or 5 µg/ml). Flow cytometry was employed to estimate cytosolic Ca²⁺-activity ([Ca²⁺]_i) from Fluo-3 fluorescence, ROS abundance from 2’,7’-dichlorodihydrofluorescein diacetate fluorescence, platelet degranulation from P-selectin abundance, integrin activation from α_IIbβ₃ integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, platelet volume from forward scatter and aggregation utilizing staining with CD9-APC and CD9-PE. Results: In the absence of CRP, ceritinib slightly, but significantly decreased [Ca²⁺]_i without significantly modifying the other measured parameters. CRP significantly increased [Ca²⁺]_i, ROS abundance, P-selectin abundance, activated α_IIbβ₃ integrin, annexin-V-binding, caspase activity as well as aggregation and decreased cell volume, all effects significantly blunted in the presence of ceritinib. Conclusions: The present observations uncover a novel, unexpected effect of ceritinib, i.e. inhibition of CRP-induced platelet activation and apoptosis.

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Inflammatory Cytokine TSLP Stimulates Platelet Secretion and Potentiates Platelet Aggregation via a TSLPR-Dependent PI3K/Akt Signaling Pathway

Cited by 25 publications

References 45 publications

Enhanced Store-Operated Calcium Entry in Platelets is Associated with Peripheral Artery Disease in Type 2 Diabetes

Enhanced Store-Operated Calcium Entry in Platelets is Associated with Peripheral Artery Disease in Type 2 Diabetes

Chorein Sensitive Dopamine Release from Pheochromocytoma (PC12) Cells

Inhibition of Collagen Related Peptide Induced Platelet Activation and Apoptosis by Ceritinib

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