Abstract
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases, such as atherosclerosis. HHcy promotes atherogenesis by modifying the histone methylation patterns and miRNA regulation. In this study, we investigated the effects of homocysteine (Hcy) on the expression of enhancer of zeste homolog 2 (EZH2), and tested our hypothesis that Hcy-induced atherosclerosis is mediated by increased EZH2 expression, which is regulated by miR-92a. The levels of EZH2 and H3K27me3 were increased in the aorta of ApoE-/- mice fed a high-methionine diet for 16 weeks, whereas miR-92a expression was decreased. Over-expression of EZH2 increased H3K27me3 level and the accumulation of total cholesterol and triglycerides in the foam cells. Furthermore, upregulation of miR-92a reduced EZH2 expression in the foam cells. These data suggested that EZH2 plays a key role in Hcy-mediated lipid metabolism disorders, and that miR-92a may be a novel therapeutic target in Hcy-related atherosclerosis.
Highlights
Recent evidence has suggested that changes in the epigenetic mechanisms, such as DNA methylation [1], histone modifications [2], and micro RNA expression [3] contribute to the development of atherosclerosis
enhancer of zeste homolog 2 (EZH2) is a key component of Polycomb repressive complex 2 (PRC2), which mediates tissue-specific gene silencing through trimethylation of H3K27 [16]
Several studies have documented the involvement of EZH2 in atherosclerosis [18]; the precise role of EZH2 in atherogenesis and the molecular mechanisms remain largely unknown
Summary
Recent evidence has suggested that changes in the epigenetic mechanisms, such as DNA methylation [1], histone modifications [2], and micro RNA (miRNA) expression [3] contribute to the development of atherosclerosis. Homocysteine (Hcy), a toxic non-protein forming thiolcontaining amino acid, is formed from methionine as a result of cellular methylation reactions [4]. Some miRNAs that regulate DNA methylation and acetylation are activated during hyperhomocysteinemia (HHcy) [7]. Hcy plays an important role in posttranslational modifications by inhibiting the expression of key genes such as FABP4 [5] and ABCA1 [8]. The underlying mechanisms of epigenetic regulation in Hcy-induced atherosclerosis are poorly understood
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