title: Retinoic acid inhibits tissue factor and HMGB1 via modulation of AMPK activity in TNF-α activated endothelial cells and LPS-injected mice.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, School of Medicine Gyeongsang National University, 660-751 Jinju, South Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine Gyeongsang National University, 660-751 Jinju, South Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine Gyeongsang National University, 660-751 Jinju, South Korea.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Pharmacology, School of Medicine Gyeongsang National University, 660-751 Jinju, South Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine Gyeongsang National University, 660-751 Jinju, South Korea. Electronic address: kcchang@gnu.kr.
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002867:Chromones / Q000737:chemistry; D003470:Culture Media; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005337:Fibrin / Q000737:chemistry; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D058258:Serpin E2 / Q000378:metabolism*; D013925:Thromboplastin / Q000037:antagonists & inhibitors*; D014212:Tretinoin / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D002867:Chromones; D003470:Culture Media; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D008070:Lipopolysaccharides; D009025:Morpholines; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014212:Tretinoin; D005337:Fibrin; D013925:Thromboplastin; D019869:Phosphatidylinositol 3-Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Retinoic acid; Tissue factor