Adiponectin inhibits tissue factor expression and enhances tissue factor pathway inhibitor expression in human endothelial cells

Yi-Jian Chen; Li-Qun Zhang; Guang-Ping Wang; Hui Zeng; Ben Lü; Xu-Liang Shen; Zhi-Ping Jiang; Fang-Ping Chen

doi:10.1160/TH08-02-0124

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(02): 291-300
DOI: 10.1160/TH08-02-0124

Endothelium and Vascular Development

Schattauer GmbH

Adiponectin inhibits tissue factor expression and enhances tissue factor pathway inhibitor expression in human endothelial cells

Authors

Yi-Jian Chen

¹Department of Hematology, Xiang Ya Hospital, Central South University, ChangSha, PR China
Li-Qun Zhang

²Department of Pharmacy, ZhanJiang Central People’s Hospital, ZhanJiang GuangDong, PR China
Guang-Ping Wang

¹Department of Hematology, Xiang Ya Hospital, Central South University, ChangSha, PR China
Hui Zeng

¹Department of Hematology, Xiang Ya Hospital, Central South University, ChangSha, PR China
Ben Lü

¹Department of Hematology, Xiang Ya Hospital, Central South University, ChangSha, PR China
Xu-Liang Shen

¹Department of Hematology, Xiang Ya Hospital, Central South University, ChangSha, PR China
Zhi-Ping Jiang

¹Department of Hematology, Xiang Ya Hospital, Central South University, ChangSha, PR China
Fang-Ping Chen

¹Department of Hematology, Xiang Ya Hospital, Central South University, ChangSha, PR China

Abstract

Summary

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 of Adp on tumor necrosis factor-α (TNF-α)-induced expression of TF and TFPI in human umbilical vein endothelial cells (HU-VECs), and the signaling transduction pathways involved. It was found that Adp significantly inhibited both TF 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 of Adp 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 LY 294002, suggesting that Akt activation might inhibit TF expression induced by TNF-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 of Adp on TF expression; but the enhancement effect of Adp on the TFPI production might occur via translational rather than transcriptional regulation.

Keywords

Adiponectin - endothelial cells - tissue factor - tissue factor pathway inhibitor - Akt - PKA

Full Text

References

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