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


OBJECTIVE
The purpose of this study was to investigate whether Panax notoginseng saponins (PNS) attenuated atherosclerosis by inducing liver X receptor alpha (LXRα) expression and to elucidate the mechanisms responsible for the effects.


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 LXRα 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 LXRα antagonist. The expression of LXRα and its target genes ATP-binding cassette A1 and G1 (ABCA1, ABCG1) were determined by qRT-PCR. The transcriptional activation of the LXRα gene promoter was analyzed by a reporter assay. The NF-κB DNA binding activity and the expression of interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1) was evaluated respectively by Trans-AM NF-κB 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 LXRα was increased in rat aortas after treatment with PNS. In vitro, PNS increased LXRα mRNA levels in THP-1 macrophages. The reporter assays showed that PNS enhanced transcriptional activation of the LXRα 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-κB 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 LXRα uprergulation. The mechanisms of action included enhancement transcriptional activation of the LXRα gene promoter by PNS and subsequent upregulation of ABCA1 and ABCG1 and inhibition of NF-κB DNA binding activity.
Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Third Military Medical University, Chongqing 400038, China.
Ji-Shan
JS
Fan
Dan-Ning
DN
Liu
Gang
G
Huang
Zhi-Zhen
ZZ
Xu
Yi
Y
Jia
Hai-Gang
HG
Zhang
Xiao-Hui
XH
Li
Feng-Tian
FT
He
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053723:Panax notoginseng; D008517:Phytotherapy; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012503:Saponins / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use*
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000071518:Liver X Receptors; D016328:NF-kappa B; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D012503:Saponins; C002963:geranylgeranyl pyrophosphate