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Unsworth, A. J.; Kriek, N.; Bye, A. P.; Naran, K.; Sage, T.; Flora, G. D.; Gibbins, J. M. (2017)
Publisher: John Wiley and Sons Inc.
Journal: Journal of Thrombosis and Haemostasis
Languages: English
Types: Article
Subjects: Original Article, platelet glycoprotein GPIIb?IIIa complex, blood platelets, PPAR gamma, Original Articles, protein kinase A, PLATELETS, platelet activation
Essentials peroxisome proliferator?activated receptor ? (PPAR?) agonists inhibit platelet function. PPAR? agonists negatively regulate outside?in signaling via integrin ?IIb?3. PPAR? agonists disrupt the interaction of G?13 with integrin ?3. This is attributed to an upregulation of protein kinase A activity. Summary Background Agonists for the peroxisome proliferator?activated receptor (PPAR?) have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. Objectives Profound effects on thrombus formation led us to suspect a role for PPAR? agonists in the regulation of integrin ?IIb?3 mediated signaling. Both GPVI and GPCR signaling pathways lead to ?IIb?3 activation, and signaling through ?IIb?3 plays a critical role in platelet function and normal hemostasis. Methods The effects of PPAR? agonists on the regulation of ?IIb?3 outside?in signaling was determined by monitoring the ability of platelets to adhere and spread on fibrinogen and undergo clot retraction. Effects on signaling components downstream of ?IIb?3 activation were also determined following adhesion to fibrinogen by Western blotting. Results Treatment of platelets with PPAR? agonists inhibited platelet adhesion and spreading on fibrinogen and diminished clot retraction. A reduction in phosphorylation of several components of ?IIb?3 signaling, including the integrin ?3 subunit, Syk, PLC?2, focal adhesion kinase (FAK) and Akt, was also observed as a result of reduced interaction of the integrin ?3 subunit with G?13. Studies of VASP phosphorylation revealed that this was because of an increase in PKA activity following treatment with PPAR? receptor agonists. Conclusions This study provides further evidence for antiplatelet actions of PPAR? agonists, identifies a negative regulatory role for PPAR? agonists in the control of integrin ?IIb?3 outside?in signaling, and provides a molecular basis by which the PPAR? agonists negatively regulate platelet activation and thrombus formation.

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