title: Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction.
abstract: OBJECTIVE
  L5 is the most negatively charged subfraction of human low-density lipoprotein (LDL) and is the only subfraction of LDL capable of inducing apoptosis in cultured vascular endothelial cells (ECs) by inhibiting fibroblast growth factor-2 (FGF2) transcription. We examined whether plasma L5 levels are elevated in patients with ST-segment elevation myocardial infarction (STEMI) and whether aspirin provides epigenetic protection of human coronary artery ECs (HCAECs) exposed to L5.
  
  
  RESULTS
  Plasma L5 levels were compared between patients with STEMI (n = 10) and control subjects with chest pain syndrome but a normal coronary arteriogram (n = 5). L5 was isolated from the plasma of STEMI patients and control subjects, and apoptosis, FGF2 expression, and FGF2 promoter methylation were examined in HCAECs treated with L5 and aspirin. Plasma L5 levels were significantly higher in STEMI patients than in control subjects (P < 0.001). Treatment of HCAECs with L5 resulted in reduced survival and FGF2 expression and increased CpG methylation of the FGF2 promoter. Co-treatment of HCAECs with L5 and a physiologically relevant, low concentration of aspirin (0.2 mM) attenuated the adverse effects of L5 on HCAEC survival, FGF2 expression, and FGF2 promoter methylation. In contrast, high concentrations of aspirin (≥1.0 mM) accentuated the effects of L5.
  
  
  CONCLUSIONS
  Our results show that L5 levels are significantly increased in STEMI patients. Furthermore, L5 impairs HCAEC function through CpG methylation of the FGF2 promoter, which is suppressed in the presence of low-concentration aspirin. Our results provide evidence of a novel mechanism of aspirin in the prevention of MI.
authors.affiliation: Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Chang
authors.forename: Yi-Jie
authors.initials: YJ
authors.lastname: Chen
authors.forename: Fu-Hsiung
authors.initials: FH
authors.lastname: Chang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lu
authors.forename: Wen-Huei
authors.initials: WH
authors.lastname: Huang
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Yang
authors.forename: Yuan-Teh
authors.initials: YT
authors.lastname: Lee
authors.forename: Shwu-Fen
authors.initials: SF
authors.lastname: Chang
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Lu
authors.forename: Chu-Huang
authors.initials: CH
authors.lastname: Chen
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology*; D001483:Base Sequence; D002317:Cardiovascular Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands / Q000187:drug effects; D019610:Cytoprotection; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D002317:Cardiovascular Agents; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; C574964:low-density lipoprotein L5, human; D016222:Fibroblast Growth Factor 2; D051057:Proto-Oncogene Proteins c-akt; D001241:Aspirin
keywords: Aspirin; DNA methylation; Genes; Lipoproteins; Myocardial infarction