title: Increased plasma S-adenosylhomocysteine-accelerated atherosclerosis is associated with epigenetic regulation of endoplasmic reticulum stress in apoE-/- mice.
abstract: OBJECTIVE
  S-Adenosylhomocysteine (SAH) is a better predictor of cardiovascular disease than homocysteine is, and it has been implicated in mediating the pathogenicity of hyperhomocysteinemia in atherosclerosis via an epigenetic mechanism. However, the underlying mechanism remains unclear. Here, we tested the hypothesis whether the effect of SAH on atherosclerosis is involved in epigenetic regulation of endoplasmic reticulum stress.
  
  
  RESULTS
  A total of 48 apolipoprotein E-deficient mice at 8 weeks were randomly divided into 4 groups (n=12 for each group). The control group was fed a conventional diet, the adenosine dialdehyde group was fed a diet that was supplemented with the SAH hydrolase inhibitor adenosine dialdehyde, and the other 2 groups were intravenously injected with a retrovirus that expressed either SAH hydrolase short hairpin RNA or scrambled short hairpin RNA semiweekly for 16 weeks. Plasma SAH levels and atherosclerotic lesion size were significantly increased in adenosine dialdehyde and SAH hydrolase short hairpin RNA groups when compared with control group. Expression of endoplasmic reticulum stress markers glucose-regulated protein-78 and CEBP-homologous protein was significantly increased in the mice with elevated plasma SAH levels. Moreover, plasma SAH was negatively associated with a decrease in the expression of trimethylated histone H3 lysine 9 and histone methyltransferases. Chromatin immunoprecipitation assays showed a significant decrease in trimethylated histone H3 lysine 9 occupancy at the glucose-regulated protein-78 and CEBP-homologous protein promoters in mice treated with adenosine dialdehyde and SAH hydrolase short hairpin RNA when compared with control mice.
  
  
  CONCLUSIONS
  Our results suggest that elevated plasma SAH levels-accelerated atherosclerosis was associated with the activation of endoplasmic reticulum stress via modulation of histone methylation.
authors.affiliation: From the Department of Nutrition and Food Hygiene, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China (Y.X., W.H., J.Z., C.P.); and Department of Nutrition, School of Public Health, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-Sen University, Guangzhou, China (Y.X., M.X., W.L.). xyjszcdc@163.com lingwenhua2012@163.com.
authors.forename: Yunjun
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: From the Department of Nutrition and Food Hygiene, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China (Y.X., W.H., J.Z., C.P.); and Department of Nutrition, School of Public Health, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-Sen University, Guangzhou, China (Y.X., M.X., W.L.).
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: From the Department of Nutrition and Food Hygiene, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China (Y.X., W.H., J.Z., C.P.); and Department of Nutrition, School of Public Health, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-Sen University, Guangzhou, China (Y.X., M.X., W.L.).
authors.forename: Jinzhou
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Department of Nutrition and Food Hygiene, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China (Y.X., W.H., J.Z., C.P.); and Department of Nutrition, School of Public Health, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-Sen University, Guangzhou, China (Y.X., M.X., W.L.).
authors.forename: Chaoqiong
authors.initials: C
authors.lastname: Peng
authors.affiliation: From the Department of Nutrition and Food Hygiene, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China (Y.X., W.H., J.Z., C.P.); and Department of Nutrition, School of Public Health, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-Sen University, Guangzhou, China (Y.X., M.X., W.L.).
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.affiliation: From the Department of Nutrition and Food Hygiene, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China (Y.X., W.H., J.Z., C.P.); and Department of Nutrition, School of Public Health, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-Sen University, Guangzhou, China (Y.X., M.X., W.L.). xyjszcdc@163.com lingwenhua2012@163.com.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Ling
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001018:Aortic Diseases / Q000097:blood* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008297:Male; D008745:Methylation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage; D012435:S-Adenosylhomocysteine / Q000097:blood*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D001057:Apolipoproteins E; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D006657:Histones; D034741:RNA, Small Interfering; C027579:periodate-oxidized adenosine; D012435:S-Adenosylhomocysteine; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D043383:Adenosylhomocysteinase; D000241:Adenosine
keywords: S-adenosylhomocysteine; atherosclerosis; endoplasmic reticulum stress; epigenenomics