Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China; Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China; NHC Key Laboratory of Metabolic Cardiovascular Diseases Research (NingXia Medical University), Yinchuan, China.
Prenatal Diagnosis Center of Ningxia Medical University General Hospital, Yinchuan, China.
J Mol Cell Cardiol. 2020 Jan;138:34-48. doi: 10.1016/j.yjmcc.2019.11.145. Epub 2019 Nov 14.
Homocysteine (Hcy) is an independent risk factor for atherosclerosis, which is characterized by lipid accumulation in the atherosclerotic plaque. Increasing evidence supports that as the main receptor of high-density lipoprotein, scavenger receptor class B member 1 (SCARB1) is protective against atherosclerosis. However, the underlying mechanism regarding it in Hcy-mediated atherosclerosis remains unclear. Here, we found the remarkable inhibition of SCARB1 expression in atherosclerotic plaque and Hcy-treated foam cells, whereas overexpression of SCARB1 can suppress lipid accumulation in foam cells following Hcy treatment. Analysis of SCARB1 promoter showed that no significant change of methylation level was observed both in vivo and in vitro under Hcy treatment. Moreover, it was found that the negative regulation of DNMT3b on SCARB1 was due to the decreased recruitment of SP1 to SCARB1 promoter. Thus, we concluded that inhibition of SCARB1 expression induced by DNMT3b at least partly accelerated Hcy-mediated atherosclerosis through promoting lipid accumulation in foam cells, which was attributed to the decreased binding of SP1 to SCARB1 promoter. In our point, these findings will provide novel insight into an epigenetic mechanism for atherosclerosis.
同型半胱氨酸（Hcy）是动脉粥样硬化的一个独立危险因素，其特征是动脉粥样硬化斑块中的脂质积累。越来越多的证据支持高密度脂蛋白的主要受体——清道夫受体 B 型成员 1（SCARB1）对动脉粥样硬化具有保护作用。然而，在 Hcy 介导的动脉粥样硬化中，其潜在机制尚不清楚。在这里，我们发现 SCARB1 表达在动脉粥样硬化斑块和 Hcy 处理的泡沫细胞中显著受到抑制，而在 Hcy 处理后过表达 SCARB1 可以抑制泡沫细胞中的脂质积累。SCARB1 启动子分析表明，在体内和体外，Hcy 处理下均未观察到甲基化水平的显著变化。此外，研究发现 DNMT3b 对 SCARB1 的负调控是由于 SP1 与 SCARB1 启动子的结合减少所致。因此，我们得出结论，DNMT3b 抑制 SCARB1 表达至少部分通过促进泡沫细胞中的脂质积累加速了 Hcy 介导的动脉粥样硬化，这归因于 SP1 与 SCARB1 启动子的结合减少。在我们看来，这些发现将为动脉粥样硬化的表观遗传机制提供新的见解。
