miR-378启动子区DNA甲基化异常在双酚S致心肌肥厚中的作用及机制研究

Pathological cardiac hypertrophy is one of the major pathophysiological changes of various cardiovascular diseases. Bisphenol S (BPS) is an emerging environmental endocrine disrupting chemical. With the widespread exposure of BPS, the potential toxic effect of BPS on human health is becoming a hot research topic in recent years. Previously, we have showed that BPS has a toxic effect on heart. However, the role of BPS in cardiac hypertrophy is still not clear. In our preliminary data, we observed that BPS promoted hypertrophy in cardiac myocytes. We further showed that exposure to BPS significantly down-regulated the expression of miR-378, which is known as an anti-hypertrophy factor; however, such effect was reversed by DNA methyltransferase inhibitor. Therefore, we speculate that BPS may promote cardiac hypertrophy through reducing miR-378 expression by DNA methylation. In this study, we aimed to investigate the effect of BPS on cardiac hypertrophy, and to understand the molecular mechanism underlying the regulation of miR-378 expression by BPS, and to fully elucidate the specific mechanisms implicated in BPS-induced cardiac hypertrophy at the whole-animal, cellular, and molecular levels using various techniques, including echocardiography, immunofluorescence, miRNA arrays, high resolution melt analysis, and bisulfite sequencing. Our results will provide the theoretical basis and evidence for further study on BPS's cardiac toxicity and facilitate the development of therapeutic measures that protect against the cardiac risks associated with BPS exposure.

病理性心肌肥厚是多种心血管疾病的主要病理生理改变之一。双酚S作为一种新型环境内分泌干扰物，是近年来的研究热点。我们研究证实双酚S具有心脏毒性作用，但其对心肌肥厚的毒理效应及机制尚不清楚。预实验结果显示：双酚S可以诱导心肌细胞肥大。进一步研究发现，双酚S明显下调抗心肌肥厚因子miR-378的表达，而DNA甲基转移酶抑制剂可以成功逆转这一过程。由此我们推测：双酚S通过诱导miR-378启动子区DNA甲基化异常介导心肌肥厚发生。为了验证这一假设，本研究拟在动物、细胞和分子等不同层面利用超声心动图、免疫荧光、miRNA芯片、甲基化高分辨率熔解曲线分析、重亚硫酸盐测序等多种实验手段，明确双酚S与心肌肥厚的相关性；解析双酚S调控miR-378表达的分子机制；最终阐明双酚S介导心肌肥厚发生的具体机制，为双酚S的心脏毒理研究及防治提供理论和实验依据。

病理性心肌肥厚是多种心血管疾病的主要病理生理改变之一。双酚S作为一种新型环境内分泌干扰物，是近年来的研究热点。大量研究证实双酚S具有心脏毒性作用，但其对心肌肥厚的毒理效应及机制尚不清楚。本研究通过细胞和动物模型利用超声心动图、免疫荧光、RT-PCR等多种实验手段，结果显示双酚S可以诱导心肌细胞肥大。进一步研究发现，双酚S明显下调抗心肌肥厚因子miR-378的表达，而DNA甲基转移酶抑制剂可以成功逆转这一过程。该研究阐明了双酚S介导心肌肥厚发生的具体机制，为双酚S的心脏毒理研究及防治提供了理论和实验依据。