Dimethylarginine dimethylaminohydrolase-1 is the critical enzyme for degrading the cardiovascular risk factor asymmetrical dimethylarginine.
Dimethylarginine dimethylaminohydrolase-1 is the critical enzyme for degrading the cardiovascular risk factor asymmetrical dimethylarginine.
复制标题
DOI：
10.1161/atvbaha.110.222638
复制
发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Hu X;Atzler D;Xu X;Zhang P;Guo H;Lu Z;Fassett J;Schwedhelm E;Böger RH;Bache RJ;Chen Y
本研究的目的是确定二甲基精氨酸二甲氨基水解酶-1在降解内源性一氧化氮合酶抑制剂ADMA和L-NMMA中的作用。我们建立了一个全球DDAH1基因缺陷(DDAH1NMMA)小鼠品系，以检测DDAH1ADMA和L-−/−降解过程中的作用，以及DDAH1DDAH1DNA缺失的生理后果。DDAH1−/−小鼠的血浆和组织中ADMA和L-NMMA的水平是野生型小鼠的数倍，但这些DDAH1−/−小鼠的生长发育与其野生型小鼠相似。虽然DDAH2的表达没有受到影响，但在所有受试组织中都检测不到DDAH活性。这些结果表明，DDAH1是ADMA和L-NMMA降解的关键酶。DDAH1−/−小鼠的血压比野生型小鼠高约20毫米汞柱，但在非应激条件下未发现其他心血管表型。DDAH1+/−雄性小鼠与DDAH1+/−雌性小鼠杂交，以1：2：1的预期比例产生DDAH1+/+小鼠、DDAH1+/−小鼠和DDAH1−/−小鼠，表明DDAH1不是该品系胚胎发育所必需的。我们的发现表明，DDAH1是体内代谢ADMA和L-NMMA所必需的，而DDAH2对ADMA和L-NMMA没有明显的降解作用。
The objective of this study was to identify the role of dimethylarginine dimethylaminohydrolase-1 (DDAH1) in degrading the endogenous NOS inhibitors ADMA and L-NMMA. We generated a global-DDAH1 gene deficient (DDAH1−/−) mouse strain to examine the role of DDAH1 in ADMA and L-NMMA degradation, and the physiological consequences of loss of DDAH1. Plasma and tissue ADMA and L-NMMA levels in DDAH1−/− mice were several fold higher than in wild type mice, but growth and development of these DDAH1−/− mice was similar to their wild type littermates. Although the expression of DDAH2 was unaffected, DDAH activity was undetectable in all tissues tested. These findings indicate that DDAH1 is the critical enzyme for ADMA and L-NMMA degradation. Blood pressure was ~20 mmHg higher in the DDAH1−/− mice than in wild type mice, but no other cardiovascular phenotype was found under unstressed conditions. Crossing DDAH1+/− male with DDAH1+/− female mice yielded DDAH1+/+ mice, DDAH1+/− mice and DDAH1−/− mice at anticipated ratios of 1:2:1, indicating that DDAH1 is not required for embryonic development in this strain. Our findings indicate that DDAH1 is required for metabolizing ADMA and L-NMMA in vivo, while DDAH2 had no detectable role for degrading ADMA and L-NMMA.