Abstract
Atherosclerosis is an arterial disease associated with inflammation. Hence, the discovery of novel therapeutic agents for suppressing inflammatory responses is urgent and vital for the treatment of atherosclerosis in cardiovascular diseases. The total saponins of Aralia elata (Miq.) Seem. (TAS) are the main components extracted from the Chinese traditional herb Longya Aralia chinensis L., a folk medicine used in Asian countries for treating numerous diseases, enhancing energy and boosting immunity. However, the protective effects of TAS against inflammation-triggered vascular endothelial dysfunction, a critical early event during the course of atherosclerosis, and the potential mechanisms of this protection have been not demonstrated. Accordingly, the aim of this study was to investigate the anti-inflammatory and anti-apoptotic effects and the protective mechanisms of TAS, and show how TAS ameliorates human umbilical vein endothelial cell (HUVEC) damage caused by tumour necrosis factor-α (TNF-α). The results indicated that TAS exerted cytoprotective effects by inhibiting TNF-α-triggered HUVEC apoptosis, mitochondrial membrane potential depolarisation, and the regulation of inflammatory factors (IL-6, MCP-1, and VCAM-1) while suppressing NF-κB transcription. Furthermore, this phenomenon was related to activation of the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway. Blocking the Akt pathway with LY294002, a PI3K inhibitor, reversed the cytoprotective effect of TAS against TNF-α-induced endothelial cell death. Moreover, LY294002 partially abolished the effects of TAS on the upregulation of the Bcl-2 family of proteins and the downregulation of Bax protein expression. In conclusion, the results of our study suggest that TAS suppresses the inflammation and apoptosis of HUVECs induced by TNF-α and that PI3K/Akt signalling plays a key role in promoting cell survival and anti-inflammatory reactions during this process.
Highlights
Atherosclerosis is a multifactorial chronic inflammatory vascular disorder that occurs due to increased exposure to environmental and genetic risk factors
human umbilical vein endothelial cell (HUVEC) were pretreated with TAS for 2 h, followed by a 24 h co-incubation or co-treatment with various doses of TAS and tumour necrosis factor-α (TNF-α) (50 ng/mL) in the drug administration groups; HUVECs were exposed only to TNF-α in the model groups
We first elucidated the protective effects of TAS against TNF-α-triggered vascular endothelial cell damage and demonstrated that TAS prevented endothelial dysfunction through exerting anti-inflammatory and anti-apoptotic action
Summary
Atherosclerosis is a multifactorial chronic inflammatory vascular disorder that occurs due to increased exposure to environmental and genetic risk factors. Increasing evidence indicates that the endothelial dysfunction and apoptosis caused by inflammation is a key inducer of atherosclerotic vascular disease [1]. Tumour necrosis factor (TNF-α), a critical inflammatory factor, has been shown to lead to the interaction of invading monocytes with vascular endothelial cells, which, in turn, causes endothelial apoptosis [2]. Inflammation causes iNOS and eNOS dysregulation, leading to endothelial dysfunction, which mainly manifests as an increase in adhesion molecules [5]. Activation of nuclear factor-κB (NF-κB) is indispensable for the stimulation of vascular TNF-α production and adhesion molecules, causing endothelial dysfunction under various pathological factors [6]. Activation of nuclear factor-κB (NF-κB) is indispensable for the stimulation of vascular TNF-α production and adhesion molecules, causing endothelial dysfunction under various pathological factors [6]. p65 forms heterogeneous dimers with members of the NF-κB family, and high levels of these dimers are found in the nucleus in endothelial cells, and plaques of patients with atherosclerosis [7]
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