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

Abstract

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-alpha (TNF-alpha)-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 both TF protein expression and activity in TNF-alpha-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-alpha, but had no effect on TFPI mRNA expression. The inhibitory effect of Adp on TNF-alpha-induced TF 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 IkappaB-alpha was decreased by Adp, but phosphorylation of p44/42 MAPK, SAPK/JNK, and p38 MAPK were not affected. These results suggested that Adp inhibits TF expression through inhibition of a PKA dependent nuclear factor-kappaB (NF-kappaB) signaling pathway. It was also found that adiponectin promoted Akt and AMP-activated protein kinase phosphorylation. The inhibitory effect of Adp on TNF-alpha-induced TF synthesis was abrogated in part by pretreatment with the PI3kinase inhibitor LY294002, suggesting that Akt activation might inhibit TF expression induced by TNF-alpha. 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-kappaB through stabilization of IkappaB-alpha 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.

Adiponectin inhibits palmitate-induced apoptosis through suppression of reactive oxygen species in endothelial cells: involvement of cAMP/protein kinase A and AMP-activated protein kinase

“…Intracellular cAMP levels decrease under an oxygen free radical-generating system (Raynaud et al 1997), and cAMP analogs display anti-apoptotic and antioxidant effects (Kim et al 2002, Fujita et al 2006. A substantial body of evidence suggests that adiponectin functions as an activator of cAMP in macrophages (Zhao et al 2005) and endothelial cells (Ouedraogo et al 2006, Chen et al 2008. Moreover, adiponectinmediated activation of cAMP exerts antioxidative effects as well as anti-inflammatory and anti-atherosclerotic effects (Ouchi et al 2000, Zhao et al 2005, Ouedraogo et al 2006, Chen et al 2008).…”

“…A substantial body of evidence suggests that adiponectin functions as an activator of cAMP in macrophages (Zhao et al 2005) and endothelial cells (Ouedraogo et al 2006, Chen et al 2008. Moreover, adiponectinmediated activation of cAMP exerts antioxidative effects as well as anti-inflammatory and anti-atherosclerotic effects (Ouchi et al 2000, Zhao et al 2005, Ouedraogo et al 2006, Chen et al 2008). In the current study, adiponectin activated cAMP level in HUVECs, and the beneficial effect of adiponectin was reversed by the inhibitors of cAMP and PKA suggesting that the cAMP/PKA pathway also mediates the antioxidant and anti-apoptotic effects of adiponectin.…”

Inflammation, obesity, and thrombosis

“…35 Conversely, adiponectin inhibits TNF-a-induced TF expression in human endothelial cells through inhibition of NF-kB signaling. 51 …”

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

“…In addition, Adp can inhibit endothelial nuclear factor-kappa B (NF-κB) activity stimulated by TNF-α via a cAMP-dependent pathway in human aortic endothelial cells [11]. Furthermore, we previously reported that Adp treatment could inhibit TNF-α-induced NF-kB P65 activity in HUVECs and increase the AMPK phosphorylation level [12]. Therefore, the aim of the present study was to examine whether Adp regulates TNF-α-induced PAI-1 expression via the cAMP-AMPK-NF-k-B signaling pathway.…”