Adiponectin inhibits macrophage tissue factor, a key trigger of thrombosis in disrupted atherosclerotic plaques

Objective: Adiponectin (APN) is an adipocytokine with anti-atherogenic and anti-inflammatory properties. Hypoadiponectinemia may associate with increased risk for coronary artery disease (CAD) and acute coronary syndrome (ACS). Tissue factor (TF) initiates thrombus formation and facilitates luminal occlusion after plaque rupture, a common cause of fatal ACS. This study tested the hypothesis that APN influences TF expression by macrophages (M Phi), inflammatory cells found in atheromatous plaques. Methods: Human monocyte-derived M Phi or RAW 264.7 cells transfected with TF promoter construct, pretreated with a physiological range of recombinant APN (1-10 mu g/ml), received LPS stimulation. TF mRNA and protein levels were quantified by real-time RT-PCR and ELISA. TF pro-coagulant activity was evaluated by one-step clotting assay. TF promoter activity was determined by a dual-luciferase reporter assay. Immunoblot analyses assessed intracellular signaling pathways. Results: APN treatment suppressed TF mRNA expression and protein production in LPS-stimulated human M Phi, compared to vehicle controls. APN treatment also significantly reduced TF pro-coagulant activity in lysates of LPS-stimulated human M Phi, compared to vehicle controls. Moreover, APN suppressed TF promoter activity in LPS-stimulated M Phi compared to controls. APN suppressed phosphorylation and degradation of IkB-alpha in LPS-stimulated M Phi. Conclusions: APN reduces thrombogenic potential of M Phi by inhibiting TF expression and activity. These observations provide a potential mechanistic link between low APN levels and the thrombotic complications of atherosclerosis. (C) 2012 Elsevier Ireland Ltd. All rights reserved.