Inhibition of Cellular Methyltransferases Promotes Endothelial Cell Activation by Suppressing Glutathione Peroxidase 1 Protein Expression

Barroso, Madalena; Florindo, Cristina; Kalwa, Hermann; Silva, Zélia; Turanov, Anton A.; Carlson, Bradley A.; Almeida, Isabel Tavares de; Blom, Henk J.; Gladyshev, Vadim N.; Hatfield, Dolph L.; Michel, Thomas; Castro, Rita; Loscalzo, Joseph; Handy, Diane E.

doi:10.1074/jbc.m114.549782

Cited by 48 publications

(63 citation statements)

References 66 publications

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“…Our findings suggested that ADA and SAHH shRNA treatment not only decreased SAHH activity but also inhibited SAHH expression at the transcriptional level, which is consistent with a recent study. 29 Furthermore, ADA-induced suppression of SAHH mRNA may be the result of a feedback mechanism in which excess SAH suppresses SAHH expression at the transcriptional level. Because SAH is an inhibitor of mRNA-methyltransferases, excess SAH can inhibit mRNA methylation, which is associated with mRNA stability.…”

Section: Discussionmentioning

confidence: 99%

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE ^−/− Mice

Xiao

Huang

Zhang

et al. 2015

ATVB

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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...

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Section: Discussionmentioning

confidence: 99%

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE ^−/− Mice

Xiao

Huang

Zhang

et al. 2015

ATVB

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“…SAH-induced hypomethylation of DNA, protein, and RNA has been associated with vascular disease [1–4]. Elevated homocysteine in plasma is an independent risk factor for cardiovascular diseases [5].…”

Section: Introductionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…Our findings showed that SAH-induced oxidative stress promotes an up-regulation of adhesion molecules [1], however, the molecular mechanisms by which redox changes activate inflammatory responses under excess SAH were not completely resolved. Here, we analyze the effects of SAH on human coronary artery endothelial cells (HCAEC), and demonstrate the role of SAH-mediated hypomethylation on NFkB activation and modulation of pro-inflammatory signals.…”

Section: Introductionmentioning

confidence: 99%

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

Barroso

Kao

Blom

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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S-Adenosylhomocysteine (SAH) can induce endothelial dysfunction and activation, contributing to atherogenesis; however, its role in the activation of the inflammatory mediator NFkB has not been explored. Our aim was to determine the role of NFkB in SAH-induced activation of endothelial cells. Furthermore, we examined whether SAH, as a potent inhibitor of S-adenosylmethionine-dependent methyltransferases, suppresses the function of EZH2 methyltransferase to contribute to SAH-induced endothelial cell activation. We found that excess SAH increases the expression of adhesion molecules and cytokines in human coronary artery endothelial cells. Importantly, this up-regulation was suppressed in cells expressing a dominant negative form of the NFkB inhibitor, IkB. Moreover, SAH accumulation triggers the activation of both the canonical and non-canonical NFkB pathways, decreases EZH2, and reduces histone 3 lysine 27 trimethylation. EZH2 knockdown recapitulated the effects of excess SAH on endothelial activation, i.e., it induced NFkB activation and the subsequent up-regulation of adhesion molecules and cytokines. Our findings suggest that suppression of the epigenetic regulator EZH2 by excess SAH may contribute to NFkB activation and the consequent vascular inflammatory response. These studies unveil new targets of SAH regulation, demonstrating that EZH2 suppression and NFkB activation mediated by SAH accumulation may contribute to its adverse effects in the vasculature.

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“…These effects were significantly attenuated after a preincubation with superoxide dismutase (Luo et al, 2012). A more recent study showed that an accumulation of intracellular SAH concentration decreased tRNA sec methylation, which reduced the expression of selenoprotein glutathione peroxidase-1 and increased the oxidative stress-induced inflammatory activation of endothelial cells (Barroso et al, 2014). However, it is still uncertain if SAH accumulation could directly induce inflammation in vivo and in vitro, or if inflammation mediated the effect of SAH in vascular disease.…”

Section: Other Potential Mechanismsmentioning

confidence: 96%

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

Xiao

Huang

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Inhibition of Cellular Methyltransferases Promotes Endothelial Cell Activation by Suppressing Glutathione Peroxidase 1 Protein Expression

Cited by 48 publications

References 66 publications

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE ^−/− Mice

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE ^−/− Mice

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

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

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Inhibition of Cellular Methyltransferases Promotes Endothelial Cell Activation by Suppressing Glutathione Peroxidase 1 Protein Expression

Cited by 48 publications

References 66 publications

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE −/− Mice

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE −/− Mice

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

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

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Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE ^−/− Mice

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE ^−/− Mice