Targeted metabolomic evaluation of arginine methylation and cardiovascular risks: potential mechanisms beyond nitric oxide synthase inhibition.
Targeted metabolomic evaluation of arginine methylation and cardiovascular risks: potential mechanisms beyond nitric oxide synthase inhibition.
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DOI：
10.1161/atvbaha.109.185645
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发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Hazen SL
中科院分区：
文献类型：
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作者：
Wang Z;Tang WH;Cho L;Brennan DM;Hazen SL
我们研究精氨酸甲基化的相关翻译后修饰产物与冠状动脉疾病（CAD）表型的关系。从1，011例连续同意接受择期诊断性心导管插入术的受试者中分离血浆，并研究3年时的未来主要不良心脏事件（MACE，包括心肌梗死、卒中和死亡）。血浆不对称二甲基精氨酸水平（ADMA，内源性一氧化氮合酶[NOS]抑制剂），对称二甲基精氨酸（SDMA，缺乏NOS抑制活性），N-单甲基精氨酸（MMA，一种有效的NOS抑制剂），甲基赖氨酸（甲基-赖氨酸，一种不相关的甲基化氨基酸），精氨酸及其主要催化剂（瓜氨酸和鸟氨酸）通过稳定同位素稀释HPLC和在线电喷雾串联质谱同时定量，并针对传统风险因素C-反应蛋白，和估计的肌酐清除率。高SDMA水平（校正比值比[OR] 1.6，95%CI 1.1-2.6，p<0.001）、低MMA水平（校正OR 0.5，95%CI 0.4-0.8，p=0.007）与严重阻塞性CAD患病率增加相关，但与ADMA水平无关（校正OR 1.3，95%CI 0.88-2.0，p=0.177）。SDMA水平升高（调整的风险比[HR] 2.4，95%CI 1.2-4.6，p=0.009），ADMA（校正的HR 2.2，95%CI 1.2-4.0，p=0.015），以及精氨酸甲基化的综合指数[ArgMI =0.015]。（ADMA+SDMA）/MMA]（校正HR 2.4，95%CI 1.3-4.5，p=0.006）是MACE事件的显著独立预测因子。即使在调整精氨酸的总体生物利用度后，ArgMI也可预测MACE的发生，尤其是在二级预防患者中。ADMA、SDMA和精氨酸甲基化的综合定量（以甲基化指数的形式）为接受心脏评估的稳定患者的严重阻塞性CAD和事件MACE提供了独立的风险预测。这些结果表明，直接NOS抑制以外的因素有助于甲基精氨酸和CAD结果之间的临床关联。
We examine the relationship of related post-translational modification products of arginine methylation and coronary artery disease (CAD) phenotypes. Plasma was isolated from 1,011 consecutive consenting subjects undergoing elective diagnostic cardiac catheterization, and future major adverse cardiac events (MACE, including myocardial infarction, stroke, and death) at 3 years were investigated. Plasma levels of asymmetric dimethylarginine (ADMA, endogenous nitric oxide synthase [NOS] inhibitor), symmetric dimethylarginine (SDMA, which lacks NOS inhibitory activity), N-mono-methylarginine (MMA, a potent NOS inhibitor), methyl-lysine (Methyl-Lys, an unrelated methylated amino acid), arginine and its major catabolites (citrulline and ornithine) were quantified simultaneously by stable isotope dilution HPLC with on-line electrospray ionization tandem mass spectrometry and adjusted for traditional risk factors, C-reactive protein, and estimated creatinine clearance. High SDMA levels (adjusted odds ratio [OR] 1.6, 95%CI, 1.1-2.6, p<0.001), low MMA (adjusted OR 0.5, 95%CI 0.4-0.8, p=0.007), but not ADMA (adjusted OR 1.3, 95%CI 0.88-2.0, p=0.177) were associated with increased prevalence of significantly obstructive CAD. Elevated levels of SDMA (adjusted Hazard Ratio [HR] 2.4, 95%CI 1.2-4.6, p=0.009), ADMA (adjusted HR 2.2, 95%CI 1.2-4.0, p=0.015), as well as an integrated index of arginine methylation [ArgMI = (ADMA+SDMA)/MMA] (adjusted HR 2.4, 95%CI 1.3-4.5, p=0.006) were significant independent predictors of incident MACE. ArgMI was predictive of incident MACE even following adjustments for global arginine bioavailability, particularly within secondary prevention patients. ADMA, SDMA and the integrated quantification of arginine methylation (in the form of a methylation index) provided independent risk prediction for both significantly obstructive CAD and incident MACE in stable patients undergoing cardiac evaluation. These results suggest that factors beyond direct NOS inhibition contribute to the clinical associations between methylarginines and CAD outcomes.