Abstract
Atherosclerosis is characterized by endothelial dysfunction, mainly induced by inflammation and oxidative stress. Increased reactive oxygen species (ROS) production together with increased adhesion molecules and thrombogenic tissue factor (TF) expression on endothelial cells has a key role in proatherogenic mechanisms. Therefore downmodulation of these molecules could be useful for reducing the severity of inflammation and atherosclerosis progression. Dehydrozingerone (DHZ) is a nutraceutical compound with anti-inflammatory and antioxidant activities. In this study we evaluated the ability of DHZ and its symmetric dimer to modulate hydrogen peroxide- (H2O2-) induced ROS production in human umbilical vein endothelial cells (HUVEC). We also evaluated intercellular adhesion molecule- (ICAM-) 1, vascular cell adhesion molecule- (VCAM-) 1, and TF expression in HUVEC activated by tumor necrosis factor- (TNF-) α. HUVEC pretreatment with DHZ and DHZ dimer reduced H2O2-induced ROS production and inhibited adhesion molecule expression and secretion. Of note, only DHZ dimer was able to reduce TF expression. DHZ effects were in part mediated by the inhibition of the nuclear factor- (NF-) κB activation. Overall, our findings demonstrate that the DHZ dimer exerts a potent anti-inflammatory, antioxidant, and antithrombotic activity on endothelial cells and suggest potential usefulness of this compound to contrast the pathogenic mechanisms involved in atherosclerosis progression.
Highlights
Endothelial dysfunction is considered an initial step in the pathogenesis of atherosclerosis [1, 2]
We evaluated intercellular adhesion molecule- (ICAM-) 1, vascular cell adhesion molecule- (VCAM-) 1, and tissue factor (TF) expression in human umbilical vein endothelial cells (HUVEC) activated by tumor necrosis factor- (TNF-) α
Considering that DNA binding studies have demonstrated a pivotal role of the nuclear factor- (NF-) κB, the transcription factor implicated in the regulation of many immune and inflammatory responses [46], including the induction of adhesion molecule expression [47, 48] and TF expression [49,50,51], we evaluated the possible involvement of NF-κB in the mechanisms of action of the two molecules under study
Summary
Endothelial dysfunction is considered an initial step in the pathogenesis of atherosclerosis [1, 2] It is mainly induced by inflammation and oxidative stress leading to structural and functional changes in the vascular endothelium. ICAM-1 and VCAM-1, membrane glycoproteins belonging to the immunoglobulin superfamily, mediate the adhesion of leukocytes to activated ECs by interacting with their ligands and induce the arrest of these cells at the vascular surface [6]. Due to the central role of endothelial dysfunction in atherosclerotic plaque formation and progression, the identification of novel medicinal agents able to counteract pathological functional changes of ECs is an important goal to reduce the severity of inflammation and to prevent atherosclerotic plaque development and thrombogenicity. Previous findings indicate that some classes of antioxidants may inhibit inflammatory mediators and TF expression, in part by reducing reactive oxygen species (ROS) and targeting redoxsensitive signaling pathways that modulate inflammatory and prothrombotic processes [14]
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