Cellular ADMA: regulation and action.
Cellular ADMA: regulation and action.
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DOI：
10.1016/j.phrs.2009.08.002
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发表时间：
2009-12
影响因子：
9.3
通讯作者：
Wilcox, Christopher S.
中科院分区：
文献类型：
--
作者：
Teerlink, Tom;Luo, Zaiming;Palm, Fredrik;Wilcox, Christopher S.
关键词：
不对称（NG，NG）二甲基精氨酸（ADMA）存在于血浆和细胞中。它能抑制产生一氧化氮（NO）的一氧化氮合酶（NOS）和从血浆中向细胞内NOS提供底物L-精氨酸的阳离子氨基酸转运蛋白（CAT）。因此，ADMA及其转运机制被战略性地置于调节内皮功能的位置。这可能具有相当大的临床影响，因为已经在人类受试者的高血压和慢性肾病（CKD）的起源处检测到内皮功能障碍，并且可能是大血管疾病和心血管疾病（CVD）的先兆。事实上，在许多研究中，ADMA的血浆水平增加，患者的风险，或与明显的CKD或CVD。然而，血浆中测得的ADMA水平约为0.5 μmol · l−1，可能低于抑制NOS所需的水平，因为NOS的底物L-精氨酸的浓度高于NOS的Km。然而，NOS活性可被细胞ADMA部分抑制。因此，ADMA通过蛋白质精氨酸甲基转移酶（PRMT）和蛋白质水解的细胞生产，其通过NG、NG-二甲基精氨酸二甲基氨基水解酶（DDAH）的降解以及其通过CAT的跨膜转运（其决定细胞内ADMA水平）也可以决定NOS的活化状态。这是审查的重点。它的结论是，细胞水平的ADMA可以是5- 20倍，在血浆中，并在一定范围内，可以紧张性抑制NOS。PRMT，DDAH和CAT确定细胞内NOS底物：抑制剂比（L-精氨酸：ADMA）的相对重要性可能会根据病理生理情况而变化。了解这一重要的平衡需要了解至少这三个过程，调节细胞内水平的ADMA和精氨酸。
Asymmetric (NG,NG) dimethylarginine (ADMA) is present in plasma and cells. It can inhibit nitric oxide synthase (NOS) that generates nitric oxide (NO) and cationic amino acid transporters (CAT) that supply intracellular NOS with its substrate, L-arginine from the plasma. Therefore, ADMA and its transport mechanisms are strategically placed to regulate endothelial function. This could have considerable clinical impact since endothelial dysfunction has been detected at the origin of hypertension and chronic kidney disease (CKD) in human subjects and may be a harbinger of large vessel disease and cardiovascular disease (CVD). Indeed, plasma levels of ADMA are increased in many studies of patients at risk for, or with overt CKD or CVD. However, the levels of ADMA measured in plasma of about 0.5 μmol · l−1 maybe below those required to inhibit NOS whose substrate, L-arginine, is present in concentrations manifold above the Km for NOS. However, NOS activity may be partially inhibited by cellular ADMA. Therefore, the cellular production of ADMA by protein arginine methyltransferase (PRMT) and protein hydrolysis, its degradation by NG, NG-dimethylarginine dimethylaminohydrolase (DDAH) and its transmembrane transport by CAT that determines intracellular levels of ADMA may also determine the state of activation of NOS. This is the focus of the review. It is concluded that cellular levels of ADMA can be 5- to 20-fold those in plasma and in a range that could tonically inhibit NOS. The relative importance of PRMT, DDAH and CAT for determining the intracellular NOS substrate: inhibitor ratio (L-arginine:ADMA) may vary according to the pathophysiologic circumstance. An understanding of this important balance requires knowledge of at least these three processes that regulate the intracellular levels of ADMA and arginine.
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