Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure
Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure
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DOI：
10.1161/atvbaha.112.254078
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发表时间：
2012-12-01
影响因子：
8.7
通讯作者：
Leiper, James
中科院分区：
文献类型：
--
作者：
Caplin, Ben;Wang, Zhen;Leiper, James
β-不对称二甲基精氨酸是一种内源性NO合成抑制剂，可能介导心血管疾病。丙氨酸-乙醛酸氨基转移酶-2（AGXT 2）被认为是降解不对称二甲基精氨酸的酶。我们研究了AGXT 2在体内甲基精氨酸代谢的意义，并研究了这种酶对血压的影响。方法和结果-在离体小鼠肾脏线粒体，我们显示在生理条件下的不对称dimethylarginine脱氨基。我们证明增加不对称二甲基精氨酸，减少NO，高血压的AGXT 2基因敲除小鼠。我们通过证明肾（同种异体移植物）基因表达与循环底物水平之间的反比关系以及表达与产物尿浓度之间的相关性，为AGXT 2在人类甲基精氨酸代谢中的作用提供了证据。最后，我们检查了血压全基因组关联研究的荟萃分析数据。没有观察到全基因组的显著性，但采用假设驱动的方法，rs37369的T等位基因之间存在暗示性关联。（这会导致缬氨酸-异亮氨酸取代和AGXT 2底物水平的改变）和舒张压的适度升高结论rs37369位点变异的影响尚需进一步研究，这些发现表明AGXT 2是甲基精氨酸的重要调节剂，并代表了肾脏调节血压的新机制。（Arterioscler Thromb Vasc Biol.2012;32：2892-2900.）
Objective-Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure.Methods and Results-In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesis-driven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (P=0.0052).Conclusion-Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure. (Arterioscler Thromb Vasc Biol. 2012;32:2892-2900.)