Adiponectin Inhibits TNF-?±-Activated PAI-1 Expression Via the cAMP-PKA-AMPK-NF-?oB Axis in Human Umbilical Vein Endothelial Cells

摘要

>Background: Tumor necrosis factor (TNF)-?± can upregulate the expression of plasminogen activator inhibitor (PAI)-1, an inhibitor of fibrinolysis. Adiponectin (Adp) antagonizes TNF-?± by negatively regulating its expression in various tissues. In the present study, the ability of Adp to suppress TNF-?±-induced PAI-1 upregulation and the underlying mechanisms were evaluated. Methods: Human umbilical vein endothelial cells (HUVECs) were treated with TNF-?± in the presence or absence of Adp, and PAI-1 mRNA and antigen expression, activated signaling pathways, and molecular mechanisms were analyzed by qRT-PCR and ELISA. Results: Adp decreased the TNF-?±-induced upregulation of PAI-1 mRNA and protein expression and suppressed TNF-?±-induced cAMP-PKA-AMPK inactivation. Adp also suppressed the TNF-?±-induced NF-kB binding capability on the PAI-1 promoter. Moreover, these Adp-induced effects were further enhanced or prevented by treatment with the cAMP inhibitor Rp-cAMPs or activator forskolin, respectively. Conclusions: Our data suggest that Adp abrogates TNF-?±-activated PAI-1 expression by activating cAMP-PKA-AMPK signaling to suppress NF-kB binding to the PAI-1 promoter in HUVECs. Given the antifibrotic effect of PAI-1 abrogation, Adp may be utilized as a novel agent in the treatment of fibrotic diseases.