Suppression of TLR4 activation by resveratrol is associated with STAT3 and Akt inhibition in oxidized low-density lipoprotein-activated platelets

Abstract

Resveratrol has many beneficial biological actions, including cardiovascular protection and antithrombotic effects. Whether resveratrol inhibits oxidized low-density lipoprotein (ox-LDL)-induced Toll-like receptor 4 (TLR4) expression in activated platelets remains unclear. The present study investigated the effects of resveratrol on the TLR4-mediated inflammatory response in ox-LDL-activated platelets. The results showed that resveratrol suppressed TLR4 expression in ox-LDL- and lipopolysaccharide (LPS)-activated platelets. Similar effects were found in puromycin-pretreated platelets. This suggests that TLR4 expression might be related to protein synthesis in ox-LDL- and LPS-activated platelets. Further analysis confirmed that resveratrol attenuated the ox-LDL-induced phosphorylation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3). A mechanistic analysis indicated that the inhibitory effect of resveratrol on TLR4 expression was associated with the suppression of Akt phosphorylation. The combination of resveratrol and the PI3K inhibitor LY294002 had a synergistic effect on the inhibition of Akt phosphorylation and TLR4 expression. Moreover, resveratrol recovered sirtuin 1 expression and adenosine monophosphate-activated protein kinase phosphorylation, which was reduced by ox-LDL treatment. Furthermore, the platelet function analysis showed that resveratrol (100 μM) reduced platelet aggregation and adhesion and CD40 ligand/platelet factor 4 secretion in ox-LDL-treated platelets. Altogether, the present findings show that resveratrol inhibits the TLR4-mediated inflammatory response in ox-LDL-activated platelets, which may contribute to the treatment of thrombosis and atherosclerosis.