- •RA reduced TF expression via AMPK-dependent way in TNF-α-activated ECs.
- •PI3K inhibitor inhibited p-AMPK by RA but compound C unaffected p-Akt by RA.
- •RA inhibited NF-kB activity by inhibition of IkB degradation in TNF-activated ECs.
- •RA reduced HMGB1 in TNF-α-activated ECs in PI3K and AMPK-sensitive manners.
- •RA decreased fibrin deposition in liver, serum prothrombotic factors in LPS- mice.
Retinoic acid (RA) is the active vitamin A derivative and has diverse immunomodulatory actions. We hypothesized that RA reduces prothrombotic mediators such as tissue factor (TF) in endothelial cells during inflammatory conditions via an AMPK-dependent pathway, which attenuates cardiovascular complications.
RA significantly increased AMPK and Akt phosphorylation in a time- and concentration-dependent manner in endothelial cells (EC). RA downregulated TF expression at the transcriptional and translational levels in TNF-α activated ECs, which was reversed by the silencing of AMPK and transfection of DN-AMPK. Interestingly, the PI3-kinase inhibitor LY294002 reversed the RA effect on TF expression. Increased AMPK phosphorylation by RA was inhibited by LY294002. However, increased Akt phosphorylation was not reduced by compound C, indicating that PI3K/Akt signaling modulates AMPK activity. In addition, RA reduced HMGB1 release in TNF-α activated ECs, which was reversed by both LY294001 and siAMPK. Importantly, administration of RA (1 mg/kg) significantly reduced blood TF activity, circulating HMGB1 and PAI-1 levels and expression of hepatic TF mRNA as well as fibrin deposition in LPS (5 mg/kg)-injected mice.
Taken together, the activation of PI3K/Akt by RA modulates AMPK activity in ECs and plays a crucial role in the inhibition of coagulatory factors such as TF, PAI-1, and HMGB1 in inflammatory conditions.
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Published online: June 17, 2015
Accepted: June 16, 2015
Received in revised form: May 15, 2015
Received: October 22, 2014
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.