Panax notoginseng saponins attenuate atherosclerosis via reciprocal regulation of lipid metabolism and inflammation by inducing liver X receptor alpha expression
Panax notoginseng saponins attenuate atherosclerosis via reciprocal regulation of lipid metabolism and inflammation by inducing liver X receptor alpha expression
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DOI：
10.1016/j.jep.2012.05.053
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发表时间：
2012-08-01
影响因子：
5.4
通讯作者：
He, Feng-Tian
中科院分区：
文献类型：
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作者：
Fan, Ji-Shan;Liu, Dan-Ning;He, Feng-Tian
民族药理学相关性：三七（伯克。）F.H.在亚洲，包括中国，日本和韩国，陈已被用作心血管疾病传统医学的保健产品和天然药物超过1000年。三七总皂苷（Panax notoginseng saponins，PNS）是从三七中提取的主要有效成分。本研究的目的：探讨三七总皂苷（Panax notoginseng saponins，PNS）是否通过诱导肝脏X受体α（Xreceptor alpha）而减轻动脉粥样硬化（LXR alpha）表达并阐明该效应的机制。材料和方法：AS大鼠每天腹腔注射PNS（100 mg/kg）一次，苏丹IV染色观察主动脉病理变化。通过Western印迹分析测量主动脉壁中LXR α的表达。THP-1巨噬细胞在存在或不存在香叶基香叶基焦磷酸铵盐（GGPP）（一种LXR α拮抗剂）的情况下与PNS一起培养。通过qRT-PCR测定LXR α及其靶基因ATP结合盒A1和G1（ABCA 1、ABCG 1）的表达。通过报告基因测定分析LXR α基因启动子的转录激活。用ELISA法检测PNS和GGPP对LPS刺激的THP-1巨噬细胞NF-κ B DNA结合活性及白细胞介素（IL）-6、单核细胞趋化蛋白-1（MCP-1）表达的影响。PNS治疗后，LXR α表达增加。在体外，PNS增加THP-1巨噬细胞中的LXR α mRNA水平。报告基因分析表明，三七总皂苷增强了LXR α基因启动子的转录激活，并导致ABCA 1和ABCG 1表达上调。这种上调可以通过用GGPP处理来逆转。此外，PNS抑制NF-κ B B DNA结合活性，并减少LPS刺激的THP-1巨噬细胞中IL-6和MCP-1的分泌。结论：PNS对AS的抑制作用可能与LXR α表达上调有关。其作用机制包括通过PNS增强LXR α基因启动子的转录激活，随后上调ABCA 1和ABCG 1以及抑制NF-κ B DNA结合活性。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
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.