Böger R H, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Böger S M
Institute of Clinical Pharmacology, Hannover Medical School, Germany.
Circ Res. 2000 Jul 21;87(2):99-105. doi: 10.1161/01.res.87.2.99.
Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor. It is formed by protein arginine N-methyltransferases (PRMTs), which utilize S-adenosylmethionine as methyl group donor. ADMA plasma concentration is elevated in hypercholesterolemia, leading to endothelial dysfunction and producing proatherogenic changes of endothelial cell function. Four different isoforms of human PRMTs have been identified. Because the release of ADMA from human endothelial cells is increased in the presence of native or oxidized LDL cholesterol, we investigated the potential involvement of PRMT activity and gene expression in this effect. We found that the production of ADMA by human endothelial cells is upregulated in the presence of methionine or homocysteine and inhibited by either of the methyltransferase inhibitors S-adenosylhomocysteine, adenosine dialdehyde, or cycloleucine. This effect is specific for ADMA but not symmetrical dimethylarginine. The upregulation of ADMA release by native and oxidized LDL is abolished by S-adenosylhomocysteine and by the antioxidant pyrrollidine dithiocarbamate. Furthermore, a methyl-(14)C label is transferred from S-adenosylmethionine to ADMA but not symmetrical dimethylarginine, in human endothelial cells. The expression of PRMTs is upregulated in the presence of native or oxidized LDL. Our data suggest that the production of ADMA by human endothelial cells is regulated by S-adenosylmethionine-dependent methyltransferases. This activity is upregulated by LDL cholesterol, which may be due in part to the enhanced gene expression of PRMTs. In concentrations reached by stimulation of methyltransferases (5 to 50 micromol/L), ADMA significantly inhibited the formation of (15)N-nitrite from L-[guanidino-(15)N(2)]arginine. These findings suggest a novel mechanism by which ADMA concentration is elevated in hypercholesterolemia, leading to endothelial dysfunction and atherosclerosis.
不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶抑制剂。它由蛋白质精氨酸N-甲基转移酶（PRMTs）生成，PRMTs利用S-腺苷甲硫氨酸作为甲基供体。高胆固醇血症时ADMA血浆浓度升高，导致内皮功能障碍并产生内皮细胞功能的促动脉粥样硬化改变。已鉴定出人类PRMTs的四种不同亚型。由于在天然或氧化型低密度脂蛋白胆固醇存在时，人内皮细胞中ADMA的释放增加，我们研究了PRMT活性和基因表达在这种效应中的潜在作用。我们发现，在甲硫氨酸或同型半胱氨酸存在时，人内皮细胞中ADMA的生成上调，而被甲基转移酶抑制剂S-腺苷同型半胱氨酸、腺苷二醛或环亮氨酸抑制。这种效应是ADMA特有的，而非对称二甲基精氨酸则无此效应。S-腺苷同型半胱氨酸和抗氧化剂吡咯烷二硫代氨基甲酸盐可消除天然和氧化型低密度脂蛋白对ADMA释放的上调作用。此外，在人内皮细胞中，甲基-（14）C标记从S-腺苷甲硫氨酸转移至ADMA，而非对称二甲基精氨酸则无此现象。在天然或氧化型低密度脂蛋白存在时，PRMTs的表达上调。我们的数据表明，人内皮细胞中ADMA的生成受S-腺苷甲硫氨酸依赖性甲基转移酶调控。这种活性被低密度脂蛋白胆固醇上调，这可能部分归因于PRMTs基因表达增强。在甲基转移酶刺激所达到的浓度（5至50微摩尔/升）下，ADMA显著抑制L-[胍基-（15）N（2）]精氨酸生成（15）N-亚硝酸盐。这些发现提示了一种新机制，通过该机制高胆固醇血症时ADMA浓度升高，导致内皮功能障碍和动脉粥样硬化。
