Jia Su-Jie, Jiang De-Jian, Hu Chang-Ping, Zhang Xiao-Hong, Deng Han-Wu, Li Yuan-Jian
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Xiang-Ya Road #110, Changsha 410078, China.
Vascul Pharmacol. 2006 Mar;44(3):143-8. doi: 10.1016/j.vph.2005.09.005. Epub 2005 Nov 23.
Recent studies suggested that endothelium is a main source of reactive oxygen species (ROS) and the major source was via NADPH oxidase pathway. Various stimuli including lysophosphatidylcholine (LPC), a major component of oxidized low-density lipoprotein (ox-LDL), can enhance the activity of NADPH oxidase and lead to a marked ROS generation. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthase (NOS) inhibitor, which is synthesized by protein arginine methyltransferase I (PRMT I) and degraded by dimethylarginine dimethylaminohydrolase (DDAH) in endothelial cells. Much evidence showed that ADMA was closely related to endothelial dysfunction. Our previous study showed that LPC elevated ADMA level in endothelial cells via increasing oxidative stress, but the precise cellular mechanism is not defined yet. The present study was to explore the mechanism of NADPH oxidase in LPC-induced elevation of ADMA. In LPC-treated endothelial cells, the ROS production, cell viability, ADMA and NO levels, the activity of DDAH and expression of PRMT I were detected. Treatment with LPC (10 microg/ml) for 24 h markedly increased intracellular ROS production, the expression of PRMT I, level of ADMA, decreased the concentration of NO and the activity of DDAH. These effects were attenuated by diphenyliodonium, the NADPH oxidase inhibitor. In summary, the present results suggested that LPC-induced elevation of ADMA was due to reduction of DDAH activity and the up-regulation of PRMT expression by stimulation of ROS production via NADPH oxidase pathway.
近期研究表明，内皮细胞是活性氧（ROS）的主要来源，且主要通过NADPH氧化酶途径产生。包括溶血磷脂酰胆碱（LPC）（氧化型低密度脂蛋白（ox-LDL）的主要成分）在内的多种刺激因素，可增强NADPH氧化酶的活性并导致大量ROS生成。不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮（NO）合酶（NOS）抑制剂，由蛋白精氨酸甲基转移酶I（PRMT I）在内皮细胞中合成，并由二甲基精氨酸二甲胺水解酶（DDAH）降解。大量证据表明，ADMA与内皮功能障碍密切相关。我们之前的研究表明，LPC通过增加氧化应激来提高内皮细胞中ADMA的水平，但具体的细胞机制尚未明确。本研究旨在探讨NADPH氧化酶在LPC诱导的ADMA升高过程中的作用机制。检测了LPC处理的内皮细胞中ROS的产生、细胞活力、ADMA和NO水平、DDAH的活性以及PRMT I的表达。用LPC（10微克/毫升）处理24小时后，细胞内ROS的产生、PRMT I的表达、ADMA的水平显著增加，NO的浓度和DDAH的活性降低。这些作用被NADPH氧化酶抑制剂二苯基碘鎓减弱。综上所述，目前的结果表明，LPC诱导的ADMA升高是由于DDAH活性降低以及通过NADPH氧化酶途径刺激ROS产生导致PRMT表达上调所致。
