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

Abstract

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 (MΦ), inflammatory cells found in atheromatous plaques. Methods Human monocyte-derived MΦ or RAW 264.7 cells transfected with TF promoter construct, pretreated with a physiological range of recombinant APN (1–10 µg/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 MΦ, compared to vehicle controls. APN treatment also significantly reduced TF pro-coagulant activity in lysates of LPS-stimulated human MΦ, compared to vehicle controls. Moreover, APN suppressed TF promoter activity in LPS-stimulated MΦ compared to controls. APN suppressed phosphorylation and degradation of IκB-α in LPS-stimulated MΦ. Conclusions APN reduces thrombogenic potential of MΦ by inhibiting TF expression and activity. These observations provide a potential mechanistic link between low APN levels and the thrombotic complications of atherosclerosis.

Chemerin is a novel biomarker of acute coronary syndrome but not of stable angina pectoris

“…Therefore, chemerin may be involved in different stages of atherosclerosis through regulating the migration of macrophage. In contrary, accumulating evidence demonstrated that adiponectin not only suppresses foam cell transformation but also inhibits the pro-coagulant activity of macrophage [37]. In the present study, a high level of chemrin and a low level of adiponectin were detected in ACS, suggesting the imbalance of pro-inflammatory/anti-inflammatory adipokines may be associated with the presence of ACS by regulation the activity of macrophage.…”

Total Adiponectin Is Inversely Associated with Platelet Activation and CHA2DS2-VASc Score in Anticoagulated Patients with Atrial Fibrillation

“…Evidence derived from the in vitro study suggested that APN was able to inhibit the macrophage tissue factor, a key molecule promoting thrombus formation in disrupted plaques [29]. In APN-knockout mice, APN deficiency was associated with enhanced thrombus formation and platelet aggregation [11].…”

Mechanisms of thrombosis in obesity

“…Adiponectin, one of the most abundant adipokines, is capable of reducing leukocyte–endothelial interactions [48,49] and inhibiting smooth muscle cell proliferation [50]. Adiponectin also stimulates nitric oxide production in endothelial cells, induces the synthesis of the anti-inflammatory cytokine IL-10 in macrophages [51], and inhibits tissue factor expression in both endothelial cells and macrophages [52,53 ▪ ]. Unfortunately, plasma levels of adiponectin tend to decrease as obesity progresses [30].…”