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 dialdehyde group was fed a diet that was supplemented with the SAH hydrolase inhibitor adenosine dialdehyde, 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 dialdehyde 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 dialdehyde 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. Xiao et al SAH and Atherosclerosis 61factor 6 also plays a key role in the production of chaperones that facilitate the repair process, including glucose-regulated protein-78 (GRP78). Upregulation of PKR-like ER kinase increases the levels of activating transcription factor 4 and CEBP-homologous protein (CHOP), a potent inducer of apoptosis.12 Numerous studies have shown that homocysteine may promote atherosclerosis through the activation of ER stress.13,14 However, there is no direct evidence that homocysteine, and not SAH, is responsible for this effect on ER stress, and no precise mechanisms have been described.SAH is produced as a product of methylation reactions involving S-adenosylmethionine (SAM) as the methyl donor, including the methylation of DNA, histone, and other proteins. 15 The ratio of SAM/SAH has been frequently used as an indicator of the cellular methylation potential. 16 Histones can be methylated on either lysine (K) or arginine (R) residues. Lysine residues can be monomethylated, dimethylated, or trimethylated in vivo. It has been reported that trimethylated histone H3 K4 (3meH3K4) is strongly ass...

Genomic Control of Upregulation of GRP78 Expression for Promotion of Neurite Elongation and Attenuation of Cell Death via PKA-Mediated Signaling in PC12 Cells

“…The promoter activity of GRP78 has been shown to be mediated through epigenetic regulation [18,19]. We did not find evidence for this activity, but histone modification or DNA methylation may be involved in neurite elongation and cell survival via upregulation of GRP78 expression.…”

S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation

“…Elevated homocysteine in plasma is an independent risk factor for cardiovascular diseases [5]. We and others have suggested that SAH is a key mediator of homocysteine-associated atherogenesis [1,6,7]. Our previous studies show that SAH can induce endothelial cell dysfunction and activation by decreasing nitric oxide production and increasing oxidative stress and leukocyte adhesion [1,8].…”

Role of S-adenosylhomocysteine in cardiovascular disease and its potential epigenetic mechanism

“…This might be mediated by SAH-reduced occupancy of 3meH3K4 at the promoters of these genes. In contrast, Xiao et al (2015) observed no effect of plasma SAH accumulation on 3meH3K4 in an animal model of atherosclerosis. Furthermore, Esfandiari et al (2010) reported that elevated hepatic SAH levels were associated with decreased occupancy of 3meH3K9 at the promoters of ER stress-related genes in mice with alcoholic liver injury.…”

“…They found early atherosclerotic lesion areas were also increased in these mice. Next, Xiao et al (2015) treated apoE−/− mice at 8 weeks with SAHH inhibitor and shRNA for an additional 16 weeks and found increased plasma SAH G Model No. of Pages 9 concentrations and accelerated the development of atherosclerotic lesion areas in both groups of mice.…”