title: Gypenoside XVII Prevents Atherosclerosis by Attenuating Endothelial Apoptosis and Oxidative Stress: Insight into the ERα-Mediated PI3K/Akt Pathway.
abstract: Phytoestrogens are estrogen-like compounds of plant origin. The pharmacological activities of phytoestrogens are predominantly due to their antioxidant, anti-inflammatory and lipid-lowering properties, which are mediated via the estrogen receptors (ERs): estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) and possibly G protein-coupled estrogen receptor 1 (GPER). Gypenoside XVII (GP-17) is a phytoestrogen that is widely used to prevent cardiovascular disease, including atherosclerosis, but the mechanism underlying these therapeutic effects is largely unclear. This study aimed to assess the anti-atherogenic effects of GP-17 and its mechanisms in vivo and in vitro. In vivo experiments showed that GP-17 significantly decreased blood lipid levels, increased the expression of antioxidant enzymes and decreased atherosclerotic lesion size in ApoE-/- mice. In vitro experiments showed that GP-17 significantly prevented oxidized low-density lipoprotein (Ox-LDL)-induced endothelial injury. The underlying protective mechanisms of GP-17 were mediated by restoring the normal redox state, up-regulating of the ratio of Bcl-2 to Bax and inhibiting the expression of cleaved caspase-3 in Ox-LDL-induced human umbilical vein endothelial cell (HUVEC) injury. Notably, we found that GP-17 treatment predominantly up-regulated the expression of ERα but not ERβ. However, similar to estrogen, the protective effect of GP-17 could be blocked by the ER antagonist ICI182780 and the phosphatidylinositol 3-kinase (PI3K) antagonist LY294002. Taken together, these results suggest that, due to its antioxidant properties, GP-17 could alleviate atherosclerosis via the ERα-mediated PI3K/Akt pathway.
authors.affiliation: Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. yangyongyao168@sina.com.|Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China. yangyongyao168@sina.com.|Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China. yangyongyao168@sina.com.|Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China. yangyongyao168@sina.com.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. hjzforever@126.com.|Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China. hjzforever@126.com.|Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China. hjzforever@126.com.|Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China. hjzforever@126.com.
authors.forename: Haijing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. yluo@implad.ac.cn.|Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China. yluo@implad.ac.cn.|Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China. yluo@implad.ac.cn.|Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China. yluo@implad.ac.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. zhangjingyi707@126.com.|Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China. zhangjingyi707@126.com.|Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China. zhangjingyi707@126.com.|Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China. zhangjingyi707@126.com.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. mwang@implad.ac.cn.|Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China. mwang@implad.ac.cn.|Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China. mwang@implad.ac.cn.|Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China. mwang@implad.ac.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Guilin Medical University, Guilin 541000, Guangxi, China. liaoping555@163.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Liao
authors.affiliation: Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. lcao@implad.ac.cn.|Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China. lcao@implad.ac.cn.|Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China. lcao@implad.ac.cn.|Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China. lcao@implad.ac.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. pguo@implad.ac.cn.|Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China. pguo@implad.ac.cn.|Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China. pguo@implad.ac.cn.|Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China. pguo@implad.ac.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. gbsun@implad.ac.cn.|Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China. gbsun@implad.ac.cn.|Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China. gbsun@implad.ac.cn.|Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China. gbsun@implad.ac.cn.
authors.forename: Guibo
authors.initials: G
authors.lastname: Sun
authors.affiliation: Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China. xbsun@implad.ac.cn.|Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China. xbsun@implad.ac.cn.|Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China. xbsun@implad.ac.cn.|Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing 100193, China. xbsun@implad.ac.cn.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D029774:Gynostemma / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D047628:Estrogen Receptor alpha; D008077:Lipoproteins, LDL; D010936:Plant Extracts; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C474918:gypenoside; C099252:oxidized low density lipoprotein; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3
keywords: apoptosis; atherosclerosis; estrogen receptors; gypenoside XVII; oxidative damage