Panax notoginseng saponins attenuate atherosclerosis via reciprocal regulation of lipid metabolism and inflammation by inducing liver X receptor alpha expression

Ethnopharmacological relevance: Panax notoginseng (Burk.) F.H. Chen has been used as a health product and natural remedy in traditional medicine for cardiovascular diseases for more than 1000 years in Asia, including China, Japan, and Korea. Panax notoginseng saponins (PNS) are the major effective ingredients extracted from Panax notoginseng. Aim of the study: The purpose of this study was to investigate whether Panax notoginseng saponins (PNS) attenuated atherosclerosis by inducing liver X receptor alpha (LXR alpha) expression and to elucidate the mechanisms responsible for the effects. Materials and methods: The AS rats were treated once daily with PNS (100 mg/kg, i.p.), and pathological changes in the aorta were observed using Sudan IV staining. The expression of LXR alpha in the aortic wall was measured by Western blot analysis. THP-1 macrophages were cultured with PNS in the presence or absence of geranylgeranyl pyrophosphate ammonium salt (GGPP), an LXR alpha antagonist. The expression of LXR alpha and its target genes ATP-binding cassette A1 and G1 (ABCA1, ABCG1) were determined by qRT-PCR. The transcriptional activation of the LXR alpha gene promoter was analyzed by a reporter assay. The NF-kappa B DNA binding activity and the expression of interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1) was evaluated respectively by Trans-AM NF-kappa B ELISA and ELISA in THP-1 macrophages that were stimulated with LPS after treatment with PNS and GGPP. Results: PNS treatment alleviated the typical pathological changes associated with atherosclerosis in rats. The expression of LXR alpha was increased in rat aortas after treatment with PNS. In vitro, PNS increased LXR alpha mRNA levels in THP-1 macrophages. The reporter assays showed that PNS enhanced transcriptional activation of the LXR alpha gene promoter and led to the upregulation of ABCA1 and ABCG1 expression. This upregulation could be reversed by treatment with GGPP. Additionally, PNS inhibited NF-kappa B DNA binding activity and reduced secretion of IL-6 and MCP-1 in LPS-stimulated THP-1 macrophages. These effects could be reversed by GGPP. Conclusions: The results indicated that the PNS-mediated attenuation of AS may, at least partly, due to LXR alpha uprergulation. The mechanisms of action included enhancement transcriptional activation of the LXR alpha gene promoter by PNS and subsequent upregulation of ABCA1 and ABCG1 and inhibition of NF-kappa B DNA binding activity. (C) 2012 Elsevier Ireland Ltd. All rights reserved.