The subcellular compartmentalization of arginine metabolizing enzymes and their role in endothelial dysfunction.
The subcellular compartmentalization of arginine metabolizing enzymes and their role in endothelial dysfunction.
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DOI：
10.3389/fimmu.2013.00184
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发表时间：
2013
影响因子：
7.3
通讯作者：
Fulton D
中科院分区：
文献类型：
--
作者：
Chen F;Lucas R;Fulton D
一氧化氮（NO）的内皮产生介导内皮依赖性血管舒张并抑制血管炎症、平滑肌细胞增殖和血小板聚集。NO的产生受损是内皮功能障碍的标志，并促进心血管疾病的发展。在内皮细胞中，NO由内皮型一氧化氮合酶（eNOS）通过其底物L-精氨酸转化为L-瓜氨酸而产生。减少获得L-精氨酸已被认为是心血管疾病中eNOS活性和NO产生减少的主要机制。精氨酸酶（Arg 1和Arg 2）代谢L-精氨酸以产生L-鸟氨酸和尿素，并且已经提出精氨酸酶的表达增加是继发于L-精氨酸消耗的eNOS活性降低的机制。事实上，补充L-精氨酸和抑制血管紧张素转换酶活性已被证明可以改善内皮依赖性舒张和改善心血管疾病。然而，这种简单的关系是复杂的观察，在内皮细胞中的L-精氨酸浓度保持足够高，以支持NO的合成。因此，已经提出了将细胞内L-精氨酸亚细胞区室化为可互换性差的库，以允许局部耗尽L-精氨酸的库或口袋。与此相一致，有相当多的证据支持l-精氨酸代谢酶的亚细胞定位的重要性。在体外和体内的内皮细胞中，eNOS存在于离散的细胞内位置，并且产生NO的能力受到其在细胞内定位的严重影响。Arg 1和Arg 2也存在于不同的亚细胞环境中，并被认为差异影响内皮功能。质膜溶质转运蛋白CAT-1和精氨酸再循环酶β-琥珀酸裂解酶与eNOS共定位并促进NO释放。在此，我们强调了eNOS和精氨酸转运和代谢酶的亚细胞定位对NO释放和心血管疾病的重要性。
The endothelial production of nitric oxide (NO) mediates endothelium-dependent vasorelaxation and restrains vascular inflammation, smooth muscle cell proliferation, and platelet aggregation. Impaired production of NO is a hallmark of endothelial dysfunction and promotes the development of cardiovascular disease. In endothelial cells, NO is generated by endothelial nitric oxide synthase (eNOS) through the conversion of its substrate, l-arginine to l-citrulline. Reduced access to l-arginine has been proposed as a major mechanism underlying reduced eNOS activity and NO production in cardiovascular disease. The arginases (Arg1 and Arg2) metabolize l-arginine to generate l-ornithine and urea and increased expression of arginase has been proposed as a mechanism of reduced eNOS activity secondary to the depletion of l-arginine. Indeed, supplemental l-arginine and suppression of arginase activity has been shown to improve endothelium-dependent relaxation and ameliorate cardiovascular disease. However, this simple relationship is complicated by observations that l-arginine concentrations in endothelial cells remain sufficiently high to support NO synthesis. Accordingly, the subcellular compartmentalization of intracellular l-arginine into poorly interchangeable pools has been proposed to allow for the local depletion of pools or pockets of l-arginine. In agreement with this, there is considerable evidence supporting the importance of the subcellular localization of l-arginine metabolizing enzymes. In endothelial cells in vitro and in vivo, eNOS is found in discrete intracellular locations and the capacity to generate NO is heavily influenced by its localization inside the cell. Arg1 and Arg2 also reside in different subcellular environments and are thought to differentially influence endothelial function. The plasma membrane solute transporter, CAT-1 and the arginine recycling enzyme, arginosuccinate lyase, co-localize with eNOS and facilitate NO release. Herein, we highlight the importance of the subcellular location of eNOS and arginine transporting and metabolizing enzymes to NO release and cardiovascular disease.