Adiponectin inhibits tissue factor expression and enhances tissue factor pathway inhibitor expression in human endothelial cells
Yi-Jian Chen 1, Li-Qun Zhang 2, Guang-Ping Wang 1, Hui Zeng 1, Ben Lü 1, Xu-Liang Shen 1, Zhi-Ping Jiang 1, Fang-Ping Chen1
1 Department of Hematology, Xiang Ya Hospital, Central South University, ChangSha, PR China; 2 Department of Pharmacy, ZhanJiang Central People’s Hospital, ZhanJiang GuangDong, PR China
Tissue factor, endothelial cells, AKT, Tissue factor pathway inhibitor, Adiponectin, PKA
Tissue factor (TF) plays a pivotal role in thrombus formation and atherogenesis in acute coronary syndrome.Tissue factor pathway inhibitor (TFPI) is a specific physiological inhibitor of TF/ FVIIa complex that regulates TF-induced coagulation.Adiponectin (Adp) is an adipocyte-specific adipocytokine with anti-atherogenic and anti-diabetic properties. Adp inhibits inflammatory cytokine and adhesion molecules expression, and it can prevent endothelial dysfunction. In this study, we investigated the effects ofAdp on tumor necrosis factor-α (TNF-α)-induced expression of TF and TFPI in human umbilical vein endothelial cells (HUVECs), and the signaling transduction pathways involved. It was found that Adp significantly inhibited bothTF protein expression and activity in TNF-α-stimulated HUVECs. In the meanwhile, it increased TFPI protein expression and activity for about two folds. Adp also inhibited TF mRNA expression induced by TNF-α, but had no effect on TFPI mRNA expression. The inhibitory effect ofAdp onTNF-α-inducedTF expression was prevented by pretreatment with Rp-cAMPs, a PKA inhibitor.Adp increased intracellular cAMP content and PKA activity levels in a dose-dependent manner. Phosphorylation of IκB-α was decreased by Adp, but phosphorylation of p44/42MAPK, SAPK/ JNK, and p38MAPK were not affected.These results suggested that Adp inhibits TF expression through inhibition of a PKA dependent nuclear factor-κB (NF-κB) signaling pathway.It was also found that adiponectin promoted Akt and AMP-activated protein kinase phosphorylation. The inhibitory effect of Adp on TNF-α-induced TF synthesis was abrogated in part by pretreatment with the PI3kinase inhibitor LY294002, suggesting that Akt activation might inhibitTF expression induced byTNF-α.The inhibitory effect of Adp is almost completely abrogated by inhibition of both the cAMP/PKA pathway and PI3K/Akt pathway. In conclusion, our data indicated that inhibition of NF-κB through stabilization of IκB-α and activation of Akt phosphorylation may mediate the inhibitory effect ofAdp onTF expression; but the enhancement effect ofAdp on theTFPI production might occur via translational rather than transcriptional regulation.