Dataset Information

PPAR? agonists negatively regulate ?IIb?3 integrin outside-in signaling and platelet function through up-regulation of protein kinase A activity.

ABSTRACT: 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.

SUBMITTER: Unsworth AJ

PROVIDER: S-EPMC5396324 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PPARγ agonists negatively regulate αIIbβ3 integrin outside-in signaling and platelet function through up-regulation of protein kinase A activity.

Unsworth A J AJ Kriek N N Bye A P AP Naran K K Sage T T Flora G D GD Gibbins J M JM

Journal of thrombosis and haemostasis : JTH 20170207 2

Essentials peroxisome proliferator-activated receptor γ (PPARγ) agonists inhibit platelet function. PPARγ agonists negatively regulate outside-in signaling via integrin αIIbβ3. PPARγ agonists disrupt the interaction of Gα13 with integrin β3. This is attributed to an upregulation of protein kinase A activity.<h4>Summary</h4>Background Agonists for the peroxisome proliferator-activated receptor (PPARγ) have been shown to have inhibitory effects on platelet activity following stimulation by GPVI an ...[more]

PMID: 27896950

Similar Datasets

Project description:Seaweeds are thought to be promising candidates for functional foods and to help prevent thrombotic and related cardiovascular diseases. Codium fragile (Suringer) Hariot has been traditionally used as a culinary ingredient, and it possesses a range of biological activities, including the inhibition of platelet function. However, the mechanism of this inhibition is unclear. The aim of this study was to examine the inhibitory effect of C. fragile in platelet function. The antiplatelet activity of C. fragile on agonist-activated platelet aggregation, granule secretion, calcium mobilization, platelet spreading, and clot retraction was assessed. The phosphorylation of c-Src, Syk, PLCγ2, and several proteins involving in the αIIbβ3 integrin outside-in signaling pathway were also studied in thrombin and CRP-stimulated platelets. The antithrombotic effect was investigated in mice using ferric chloride-induced arterial thrombus formation in vivo. Transection tail bleeding time was used to evaluate whether C. fragile inhibited primary hemostasis. The main components and contents of C. fragile ethanol extract were confirmed by GC-MS analysis. C. fragile significantly impaired agonist-induced platelet aggregation granule secretion, calcium mobilization, platelet spreading, and clot retraction. Biochemical analysis revealed that C. fragile inhibited the agonist-induced activation of c-Src, Syk, and PLCγ2, as well as the phosphorylation of PI3K, AKT, and mitogen-activated protein kinases (MAPKs). The inhibitory effect of C. fragile resulted from an inhibition of platelet αIIbβ3 integrin outside-in signal transduction during cell activation. Oral administration of C. fragile efficiently blocked FeCl3-induced arterial thrombus formation in vivo without prolonging bleeding time. GC-MS analysis revealed that phytol was the main constituent and the total content of isomers was 160.8 mg/kg. Our results demonstrated that C. fragile suppresses not only the inside-out signaling of αIIbβ3 integrin but also outside-in signal transmission. Therefore, C. fragile could be an effective antiplatelet therapeutic candidate.