Homocysteine-induced extracellular superoxide dismutase and its epigenetic mechanisms in monocytes.

Abstract

Although a modest homocysteine (Hcy) elevation is associated with an increased cardiovascular risk, the underlying mechanisms whereby Hcy triggers the accumulation of cholesterol and the roles of the extracellular superoxide dismutase (EC-SOD) in the development of foam cells have not yet been elucidated. In this study, we found both increased numbers of foam cells and an accumulation of cholesterol, and the H(2)O(2) and oxidized low-density lipoprotein content also increased. Levels of EC-SOD were significantly suppressed by Hcy, however, while 5-azacytidine (AZC), a potent DNA methyltransferase (DNMT) inhibitor, increased the expression of EC-SOD. A quantitative real-time PCR of EC-SOD revealed that Hcy (100 micromol l(-1)) accelerates DNA methylation of EC-SOD, but selectively increases the activity of DNA methyl transferase 1 (DNMT1). It showed that Hcy can reduce binding of methyl CpG and binding protein 2 (MeCP2) but has no effect on the activity of DNMT3. Moreover, chromatin immunoprecipitation assays demonstrated that Hcy increased the binding of acetylated histone H3 and H4 in monocytes. Based on the fact that the binding of MeCP2 with the EC-SOD was completely suppressed by AZC and trichostatin A [TSA, a histone deacetylase (HDAC) inhibitor], it is indicated that DNA methylation and HDAC mediate the binding of MeCP2 with EC-SOD gene. In conclusion, the study found that Hcy accelerates the development of foam cells by repressing EC-SOD transcription, and that Hcy exerts this function by upregulating DNA methylation via suppression of HDAC activity and increased DNMT1 activity.

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