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.
Approach and 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 deaminase group was fed a diet that was supplemented with the SAH hydrolase inhibitor periodate-oxidized adenosine deaminase, 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 deaminase 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 deaminase 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.
- Received April 9, 2014.
- Accepted October 21, 2014.
- © 2014 American Heart Association, Inc.
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- Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE−/− MiceYunjun Xiao, Wei Huang, Jinzhou Zhang, Chaoqiong Peng, Min Xia and Wenhua LingArteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.303817, originally published October 30, 2014https://doi.org/10.1161/ATVBAHA.114.303817
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- Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE−/− MiceYunjun Xiao, Wei Huang, Jinzhou Zhang, Chaoqiong Peng, Min Xia and Wenhua LingArteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.303817, originally published October 30, 2014https://doi.org/10.1161/ATVBAHA.114.303817