Qu Kai, Ma Xiao-Feng, Li Guo-Hua, Zhang Hai, Liu Ya-Mi, Zhang Kai, Zeng Jun-Fa, Lei Jian-Jun, Wei Dang-Heng, Wang Zuo
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001 China.
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001 China; The Second Hospital Affiliated to University of South China, Hengyang 421001, Hunan, China.
Int J Biol Macromol. 2017 May;98:637-645. doi: 10.1016/j.ijbiomac.2017.02.025. Epub 2017 Feb 10.
Lipoprotein(a)[Lp(a)] is a risk factor for coronary heart diseases. However, the metabolism of this protein remains poorly understood. Efficient and specific drugs that can decrease high plasma levels of Lp(a) have not been developed yet. Vitamin C is responsible for maintaining the catalytic activity of a group of iron and 2-oxoglutarate (2OG)-dependent dioxygenases and induces the generation of 5-hydroxymethylcytosine (5hmC) via Ten-eleven translocation (Tet) dioxygenases. In addition, It has been reported vitamin C deficiency induces atherosclerosis and increases Lp(a) and apo(a) plasma levels in Lp(a)+ mice. However, the mechanism is still unclear. In this study, we investigated the effects of vitamin C on apo(a) expression and the possible molecular mechanism of vitamin C that influences apolipoprotein(a) [apo(a)] biosynthesis in HepG2 cells. Results showed that vitamin C significantly inhibited the expression and secretion levels of apo(a). Vitamin C can also increase ELK1 expression and hydroxymethylation of ELK1 promoter and the globle DNA in HepG2 cells. In addition, the effects of vitamin C inhibiting the apo(a) expression were attenuated by ELK1siRNA and Tet2siRNA. These results suggested vitamin C down-regulate apo(a) expression via Tet2-dependent DNA demethylation in HepG2 cells.
脂蛋白(a)[Lp(a)]是冠心病的一个风险因素。然而,这种蛋白质的代谢仍知之甚少。目前尚未开发出能有效降低血浆中高Lp(a)水平的特异性药物。维生素C负责维持一组铁和2-氧代戊二酸(2OG)依赖性双加氧酶的催化活性,并通过Tet双加氧酶诱导5-羟甲基胞嘧啶(5hmC)的生成。此外,有报道称维生素C缺乏会诱发动脉粥样硬化,并增加Lp(a)+小鼠的Lp(a)和载脂蛋白(a)(apo(a))血浆水平。然而,其机制仍不清楚。在本研究中,我们研究了维生素C对apo(a)表达的影响以及维生素C影响HepG2细胞中载脂蛋白(a)[apo(a)]生物合成的可能分子机制。结果表明,维生素C显著抑制apo(a)的表达和分泌水平。维生素C还可增加HepG2细胞中ELK1的表达以及ELK1启动子和基因组DNA的羟甲基化。此外,ELK1小干扰RNA(siRNA)和Tet2 siRNA可减弱维生素C抑制apo(a)表达的作用。这些结果表明,在HepG2细胞中,维生素C通过Tet2依赖性DNA去甲基化下调apo(a)的表达。