title: The comprehensive effects of hyperlipidemia and hyperhomocysteinemia on pathogenesis of atherosclerosis and DNA hypomethylation in ApoE-/- mice.
abstract: Atherosclerosis (AS) is a disease induced by multiple factors, including genetic and environmental elements. The aim of the present study is to investigate the comprehensive effects of high cholesterol, high methionine diet, and apolipoprotein E deficiency (ApoE(-/-)) on the pathogenesis of AS. ApoE(-/-) mice were fed with high cholesterol and methionine diet for 15 weeks to induce hyperlipidemia and hyperhomocysteinemia. The methylation levels of genomic DNA (gDNA) and B1 repetitive elements in aortic tissues were measured by both methylation-dependent restriction analysis and nested methylation-specific polymerase chain reaction (PCR). Methylation sequence-bias pattern was assayed by DNA methyl-accepting capacity with restriction endonuclease digestion. The mRNA expression of DNA methyltransferase-1, 3 (DNMT1, 3) was detected by real-time PCR. The concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were determined by high-performance liquid chromatography. The results showed hypomethylation of gDNA and B1 repetitive elements. The mRNA expression of DNMT1 was reduced. The levels of SAM, SAH, and SAM/SAH ratio were increased. The atherosclerotic lesion areas strongly correlated with the risk factors. The distribution of DNA demethylation was preferred to non-CpG islands, which may suggest the major impact of hypomethylation on DNA integrity and genomic instability. Overall, our data unequivocally showed that the comprehensive role of high cholesterol, high methionine diet, and ApoE(-/-) is not uniformly consistent with the role of a single risk factor. The DNA methylation pattern in AS is quite complex and depends on genetic background and many involved risk factors.
authors.affiliation: Postdoctoral Workstation, General Hospital of Ningxia Medical University, Yinchuan, China.
authors.forename: Yideng
authors.initials: Y
authors.lastname: Jiang
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: Ju
authors.initials: J
authors.lastname: Wang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Sun
authors.forename: Huihui
authors.initials: H
authors.lastname: Gong
authors.forename: Binbin
authors.initials: B
authors.lastname: Yang
authors.forename: Yingkang
authors.initials: Y
authors.lastname: Shi
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000633:toxicity; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015870:Gene Expression; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000209:etiology / Q000235:genetics*; D006949:Hyperlipidemias / Q000209:etiology / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D008055:Lipids; D014280:Triglycerides; D006710:Homocysteine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D002784:Cholesterol; D008715:Methionine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619381:Dnmt1 protein, mouse