Abstract
ICAM-1 overexpression and subsequent adhesion of leukocytes to endothelial cells play critical roles in the early stage of atherosclerosis. Danshenol A (DA) is an abietane-type diterpenoid isolated from traditional Chinese herb Salvia miltiorrhiza Bunge. The mechanisms under its regulation of adhesion of molecular expression are explored. Here, the effect of DA on TNF-α-induced ICAM-1 expression was investigated in endothelial cells. TNF-α-induced ICAM-1 expression and subsequent adhesion of monocytes, as well as elevated reactive oxygen species (ROS) generation and NOX4 expression were all significantly reversed by DA, siNOX4 and NOX4 inhibitor GKT137831. Furthermore, TNF-α-induced ICAM-1 expression, which was increased via IKKβ/IκBα-mediated activation of NF-κB p65, was also inhibited by DA. Interestingly, NOX4 overexpression suppressed the ICAM-1 expression, and this finding may be ascribed to the activation of Nrf-2. Additionally, NF-κB inhibitor PDTC, siNOX4, or DA can decrease the TNF-α-induced ICAM-1 expression and suppress the adhesion of monocytes. In all, DA inhibited TNF-α-induced ICAM-1 expression and subsequent monocyte adhesion to endothelial cells through the NOX4-dependent IKKβ/NF-κB pathway. Besides, NOX4 played dual role in regulating ICAM-1 expression via diverse signal pathway. This novel bioactivity will make DA a good candidate to be further explored for therapeutic or preventive application for atherosclerosis.
Highlights
Atherosclerosis is known as a chronic inflammatory disorder[1]
We investigated the inhibitory effect of Danshenol A (DA) on TNF-α-induced ICAM-1 expression in endothelial cells
The results demonstrated the following: (1) DA inhibited TNF-α-induced ICAM-1 expression; (2) reactive oxygen species (ROS)-dependent NF-κB signaling played an important role in this process; and (3) NOX4 served a dual role in regulating the TNF-α-induced ICAM-1 expression
Summary
Atherosclerosis is known as a chronic inflammatory disorder[1]. As an important proinflammatory cytokine, TNF-α activates endothelial cells at the site of inflammation, leading to the upregulation of endothelial cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1)[2], intercellular adhesion molecule (ICAM-1)[3], and endothelial leukocyte adhesion molecule-1 (E-selectin)[4]. We can reasonably speculate that ROS is responsible for the expression of TNF-α-induced adhesion molecules and the subsequent leukocyte accumulation. The NADPH oxidase (NOXs) family, as an important source of ROS outside the mitochondria, has been implicated in the pathophysiology of vascular diseases[15,16]. Several lines of evidence have shown that the expression of TNF-α-induced molecules is regulated at the gene level by activation of transcription factors. These transcription factors, including Nrf-1, Nrf-2, and NF-κB p65, are redox sensitive and identified to be involved in the regulation of the gene expression of leukocyte-adhesion molecules and cytokines[21,22,23]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
