title: Involvement of histone methylation in macrophage apoptosis and unstable plaque formation in methionine-induced hyperhomocysteinemic ApoE-/-mice.
abstract: OBJECTIVE
  Hyperhomocysteinemia (Hhcy) is an independent risk factor of atherosclerosis and promotes unstable plaque formation. Epigenetic mechanisms play an important role in the pathogenesis of atherosclerosis induced by Hhcy. However, the exact mechanism is still undefined. Lesional apoptotic cells and necrotic core formation contribute greatly to the progression of plaque. The present study sought to determine whether modification of histone methylation is involved in macrophage apoptosis and unstable plaque formation in the condition of Hhcy.
  
  
  METHODS
  The unstable plaque formation, lesional apoptotic cells and status of histone methylation were monitored in the aortas of Hhcy ApoE-/-mice induced by a high-methionine (HM) diet for 20weeks. Involvement of histone methylation in macrophage apoptosis and foam cell formation were assessed in macrophage Raw 264.7 cells after being challenged with homocysteine alone or in combination with the histone methylation inhibitor BIX 01294.
  
  
  RESULTS
  The unstable plaque formation and lesion apoptotic cells are increased in ApoE-/-mice supplemented with high-methionine (HM), accompanied with a decreased expression of histone H3 lysine 9 dimethylation. Hhcy increases the apoptosis of macrophages and inhibits the histone H3 lysine 9 dimethylation, as well as the expression of histone methyltransferase G9a in vitro. Inhibition of histone methylation by BIX01294 enhances macrophage apoptosis and foam cell formation in vitro.
  
  
  CONCLUSIONS
  Our data suggest that Hhcy promotes the progression of atherosclerosis via macrophage apoptosis. Histone methylation might be involved in macrophage apoptosis and unstable plaque formation in methionine induced hyperhomocysteinemic ApoE-/-mice.
authors.affiliation: Department of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750001, PR China; Institute of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Cong
authors.affiliation: Institute of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China.
authors.forename: Ru
authors.initials: R
authors.lastname: Yan
authors.affiliation: Heart Centre, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750001, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750001, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yan
authors.affiliation: Department of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750001, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.affiliation: Department of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750001, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Heart Centre, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Hou
authors.affiliation: Heart Centre, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Chen
authors.affiliation: Institute of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China; Heart Centre, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China. Electronic address: jsbxn@163.com.
authors.forename: Shaobin
authors.initials: S
authors.lastname: Jia
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D008715:Methionine / Q000009:adverse effects* / Q000494:pharmacology; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D006657:Histones; D008715:Methionine
keywords: Apoptosis; Atherosclerosis; Epigenomics; Histone methylation; Hyperhomocysteinemia