title: Myricitrin attenuates endothelial cell apoptosis to prevent atherosclerosis: An insight into PI3K/Akt activation and STAT3 signaling pathways.
abstract: Blood vessel endothelial dysfunction induced by oxidized low-density lipoprotein (ox-LDL) has been implicated in the pathogenesis of atherosclerosis and vasculopathy. The ox-LDL-elicited reactive oxygen species (ROS) release has been assumed to serve a critical function in endothelial damage. Myricitrin (from Myrica cerifera) is a natural antioxidant that has strong anti-oxidative, anti-inflammatory, and anti-nociceptive activities. However, the protective effect of myricitrin on ROS-induced endothelial cell injury and its related molecular mechanisms have never been investigated. This study demonstrates that myricitrin can inhibit ox-LDL-induced endothelial apoptosis and prevent plaque formation at an early stage in an atherosclerotic mouse model. The administration of myricitrin in vivo decreases the thickness of the vascular wall in the aortic arch of ApoE-/- mice. In vitro study shows that ox-LDL-induced human umbilical vein endothelial cell apoptosis can be reduced upon receiving myricitrin pre-treatment. Treatment with myricitrin significantly attenuated ox-LDL-induced endothelial cell apoptosis by inhibiting LOX-1 expression and by increasing the activation of the STAT3 and PI3K/Akt/eNOS signaling pathways. At the same time, our result demonstrates that myricitrin treatment optimizes the balance of pro/anti-apoptosis proteins, including Bax, Bad, XIAP, cIAP-2, and survivin. Our study suggests that myricitrin treatment can effectively protect cells from ox-LDL-induced endothelial cell apoptosis, which results in reduced atherosclerotic plaque formation. This result indicates that myricitrin can be used as a drug candidate for the treatment of cardiovascular diseases.
authors: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, 100193 Beijing, PR China.
authors: Meng
authors: M
authors: Qin
authors: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, 100193 Beijing, PR China.
authors: Yun
authors: Y
authors: Luo
authors: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, 100193 Beijing, PR China.
authors: Xiang-bao
authors: XB
authors: Meng
authors: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, 100193 Beijing, PR China.
authors: Min
authors: M
authors: Wang
authors: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Hankou Road 22, Nanjing, 210093, Jiangsu, PR China.
authors: Hong-wei
authors: HW
authors: Wang
authors: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Hankou Road 22, Nanjing, 210093, Jiangsu, PR China.
authors: Shi-yu
authors: SY
authors: Song
authors: Jilin Agricultural University, No.2888, Xincheng Street, Changchun 130021, Jilin, PR China.
authors: Jing-xue
authors: JX
authors: Ye
authors: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, 100193 Beijing, PR China.
authors: Rui-le
authors: RL
authors: Pan
authors: Department of Pharmacology, School of Basic Medical Sciences, Jilin University, Changchun 130025, Jilin, PR China.
authors: Fan
authors: F
authors: Yao
authors: Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, PR China.
authors: Ping
authors: P
authors: Wu
authors: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, 100193 Beijing, PR China. Electronic address: sunguibo@126.com.
authors: Gui-bo
authors: GB
authors: Sun
authors: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, 100193 Beijing, PR China. Electronic address: sun_xiaobo163@163.com.
authors: Xiao-bo
authors: XB
authors: Sun
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001706:Biopsy; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D058226:Plaque, Atherosclerotic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D055114:X-Ray Microtomography
chemical_list: D001057:Apolipoproteins E; D051017:Apoptosis Regulatory Proteins; D002317:Cardiovascular Agents; D005419:Flavonoids; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; C495138:Olr1 protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; C008577:myricitrin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Atherosclerosis; Endothelial cells; Myricitrin; Oxidized low-density lipoprotein; Reactive oxygen species