microRNA-152 Mediates DNMT1-Regulated DNA Methylation in the Estrogen Receptor α Gene

Background: Estrogen receptor alpha (ER alpha) has been shown to protect against atherosclerosis. Methylation of the ER alpha gene can reduce ER alpha expression leading to a higher risk for cardiovascular disease. Recently, microRNAs have been found to regulate DNA methyltransferases (DNMTs) and thus control methylation status in several genes. We first searched for microRNAs involved in DNMT-associated DNA methylation in the ER alpha gene. We also tested whether statin and a traditional Chinese medicine (San-Huang-Xie-Xin-Tang, SHXXT) could exert a therapeutic effect on microRNA, DNMT and ER alpha methylation. Methodology/Principal Findings: The ER alpha expression was decreased and ER alpha methylation was increased in LPS-treated human aortic smooth muscle cells (HASMCs) and the aorta from rats under a high-fat diet. microRNA-152 was found to be down regulated in the LPS-treated HASMCs. We validated that microRNA-152 can knock down DNMT1 in HASMCs leading to hypermethylation of the ER alpha gene. Statin had no effect on microRNA-152, DNMT1 or ER alpha expression. On the contrary, SHXXT could restore microRNA-152, decrease DNMT1 and increase ER alpha expression in both cellular and animal studies. Conclusions/Significance: The present study showed that microRNA-152 decreases under the pro-atherosclerotic conditions. The reduced microRNA-152 can lose an inhibitory effect on DNA methyltransferase, which leads to hypermethylation of the ER alpha gene and a decrease of ER alpha level. Although statin can not reverse these cascade proatherosclerotic changes, the SHXXT shows a promising effect to inhibit this unwanted signaling pathway.