Homocysteine-mediated expression of SAHH, DNMTs, MBD2, and DNA hypomethylation potential pathogenic mechanism in VSMCs.
Homocysteine (Hcy) is a well-established risk factor for atherosclerosis and may cause dysregulation of gene expression, but the characteristics and the key links involved in its pathogenic mechanisms are still poorly understood. The aim of this study was to explore (i) the effects of Hcy on DNA methylation in vascular smooth muscle cells (VSMCs) and (ii) the underlying mechanism of Hcy-induced changes in DNA methylation patterns in relation to atherosclerosis. We examined the levels of gDNA methylation, namely, the Alu and line-1 element sequences, which can serve as a surrogate marker for gDNA methylation, and also investigated the effects of Hcy on the intracellular S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) concentrations as well as the expressions of SAH hydrolase (SAHH), DNA methyltransferase3a (DNMT3a), DNMT3b, and methyl-CpG-binding domain 2 (MBD2). We found that clinically relevant levels of Hcy (0-500 microM) induced elevation of SAH, declination of SAM and SAM/SAH ratio, and reduction in expression of SAHH and MBD2, but increased the activity of DNMT3a and DNMT3b compared to the control group (p < 0.05). We found also that the genome-wide hypomethylation is a common feature of gDNA in the VSMCs cultured with Hcy. In conclusion, these results suggest that Hcy-induced DNA methylation may be an important potential pathogenic mechanism in the development of atherosclerosis, and may become a therapeutic target for preventing Hcy-induced atherosclerosis.
Yideng
Jiang
J
Department of Pathophysiology, West China College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu, China.
Jianzhong
Zhang
Z
Ying
Huang
H
Juan
Su
S
Jinge
Zhang
Z
Shenglan
Wang
W
Xiaoqun
Han
H
Shuren
Wang
W
D043383:Adenosylhomocysteinase / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000096:biosynthesis; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; C489325:MBD2 protein, human; D006710:Homocysteine; D012313:RNA; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D043383:Adenosylhomocysteinase