Dong Pengzhi, Pan Lanlan, Zhang Xiting, Zhang Wenwen, Wang Xue, Jiang Meixiu, Chen Yuanli, Duan Yajun, Wu Honghua, Xu Yantong, Zhang Peng, Zhu Yan
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, China.
The College of Life Sciences, Nankai University, Tianjin 300071, China.
J Ethnopharmacol. 2017 Feb 23;198:479-488. doi: 10.1016/j.jep.2017.01.040. Epub 2017 Jan 21.
Hawthorn (Crataegus pinnatifida Bunge) leave have been used to treat cardiovascular diseases in China and Europe. Hawthorn leave flavonoids (HLF) are the main part of extraction. Whether hawthorn leave flavonoids could attenuate the development of atherosclerosis and the possible mechanism remain unknown.
High-fat diet (HFD) mixed with HLF at concentrations of 5mg/kg and 20mg/kg were administered to apolipoprotein E (apoE) knock out mice. 16 weeks later, mouse serum was collected to determine the lipid profile while the mouse aorta dissected was prepared to measure the lesion area. Hepatic mRNA of genes involved in lipid metabolism were determined. Peritoneal macrophages were collected to study the impact of HLF on cholesterol efflux, formation of foam cell and the expression of ATP binding cassette transporter A1 (ABCA1). Besides, in vivo reverse cholesterol transport (RCT) was conducted.
HLF attenuated the development of atherosclerosis that the mean atherosclerotic lesion area in en face aortas was reduced by 23.1% (P<0.05). In mice fed with 20mg/kg HLF, Total cholesterol (TC) level was decreased by 18.6% and very low density lipoprotein cholesterol plus low density lipoprotein cholesterol (VLDLc+LDLc) level were decreased by 23.1% whereas high density lipoprotein cholesterol (HDLc) and triglyceride (TG) levels were similar compared to that of the control group. Peroxisome proliferator activated receptor alpha (PPARα) mRNA was increased by 31.2% (P<0.05) and 60.9% (P<0.05) in mice fed with 5mg/kg and 20mg/kg HLF respectively. Sterol regulatory element binding protein-1c (SREBP-1c) was decreased by 59.3% in the group of 20mg/kg. Carnitine palmitoyl transferase 1 (CPT-1) mRNA level of 20mg/kg group was induced 66.7% (P<0.05). Superoxide dismutase 1 and 2 (SOD1 and SOD2) mRNA were induced 25.4% (P<0.05) and 71.4% (P<0.05) while induced by 36.3% (P<0.05) and 73.2% (P<0.05) in group of 20mg/kg. Glutathione peroxidase 3 (Gpx3) mRNA in the group of 20mg/kg was induced by 96.7% (P<0.05). Hepatic hydroxymethylglutaryl CoA reductase (HMG-CoAR) expression was as same level as the control group while LDL receptor (LDLR) mRNA and protein were induced by 84.2% (P<0.05) and 98.8% (P<0.05) in group of 20mg/kg. HLF inhibit the formation of foam cell by 27.9% (P<0.05) in the dosage of 25μg/ml, and 33.3% (P<0.05) in the dosage of 50μg/ml. HLF increased the reverse cholesterol transport (RCT) in vivo.
Hawthorn leave flavonoids can slow down the development of atherosclerosis in apoE knockout mice via induced expression of genes involved in antioxidant activities, inhibition of the foam cell formation and promotion of RCT in vivo, which implies the potential use in the prevention of atherosclerosis.
在中国和欧洲，山楂（山里红）叶已被用于治疗心血管疾病。山楂叶黄酮（HLF）是提取物的主要成分。山楂叶黄酮是否能减缓动脉粥样硬化的发展及其可能的机制尚不清楚。
将浓度为5mg/kg和20mg/kg的HLF与高脂饮食（HFD）混合后给予载脂蛋白E（apoE）基因敲除小鼠。16周后，收集小鼠血清以测定血脂水平，同时解剖小鼠主动脉以测量病变面积。测定参与脂质代谢的基因的肝脏mRNA水平。收集腹腔巨噬细胞以研究HLF对胆固醇流出、泡沫细胞形成和ATP结合盒转运蛋白A1（ABCA1）表达的影响。此外，还进行了体内逆向胆固醇转运（RCT）。
HLF减缓了动脉粥样硬化的发展，主动脉正面的平均动脉粥样硬化病变面积减少了23.1%（P<0.05）。在喂食20mg/kg HLF的小鼠中，总胆固醇（TC）水平降低了18.6%，极低密度脂蛋白胆固醇加低密度脂蛋白胆固醇（VLDLc+LDLc）水平降低了23.1%，而高密度脂蛋白胆固醇（HDLc）和甘油三酯（TG）水平与对照组相似。在分别喂食5mg/kg和20mg/kg HLF的小鼠中，过氧化物酶体增殖物激活受体α（PPARα）mRNA分别增加了31.2%（P<0.05）和60.9%（P<0.05）。在20mg/kg组中，固醇调节元件结合蛋白-1c（SREBP-1c）降低了59.3%。20mg/kg组的肉碱棕榈酰转移酶1（CPT-1）mRNA水平升高了66.7%（P<0.05）。超氧化物歧化酶1和2（SOD1和SOD2）mRNA在20mg/kg组中分别升高了25.4%（P<0.05）和71.4%（P<0.05），在5mg/kg组中分别升高了36.3%（P<0.05）和73.2%（P<0.05）。20mg/kg组的谷胱甘肽过氧化物酶3（Gpx3）mRNA升高了96.7%（P<0.05）。肝脏羟甲基戊二酰辅酶A还原酶（HMG-CoAR）表达与对照组水平相同，而在20mg/kg组中，低密度脂蛋白受体（LDLR）mRNA和蛋白分别升高了84.2%（P<0.05）和98.8%（P<0.05）。HLF在25μg/ml剂量下抑制泡沫细胞形成27.9%（P<0.05），在50μg/ml剂量下抑制33.3%（P<0.05）。HLF增加了体内逆向胆固醇转运（RCT）。
山楂叶黄酮可通过诱导参与抗氧化活性的基因表达、抑制泡沫细胞形成和促进体内RCT，减缓apoE基因敲除小鼠动脉粥样硬化的发展，这表明其在预防动脉粥样硬化方面具有潜在用途。
