关键词： 6-pyruvoyl tetrahydropterin synthase 7,8-dihydroneopterin 30 triphosphate 8-Oxoguanine DNA glycosylase ADMA AF AGXT2 AP-1 ARE AT ApoE-KO AscH(−) BH(3) BH(4) CAAs CAT CATs CR CV CaM Cardiovascular disease DDAHs DHFR DHPR DM DMA DMGV DNTP ERK FAD FMN FOS FOXO Finkel–Biskis–Jinkins osteosarcoma Free radicals GP GPx GSH GTP GTP cyclohydrolase 1 GTP-CH HIF HSP JNK LDL LTL MAO MAPK MDA MT N(G)-monomethyl-l-arginine N-nitro-l-arginine N-omega-hydroxy-l-arginine NADPH NADPH oxidase NF-κB NO NO inhibitors NO synthases NOHA NOX NTPH Nrf2 OGG1 OS PAH PCD PRMT PTPS Prx RNS ROS Ref-1 S-adenosyl-l-homocysteine S-adenosyl-l-methionine SAH SAM SDMA SOD SR TH TocH Trx UA activator protein 1 alanine-glyoxylate aminotransferase 2 angiotensin antioxidant response element apolipoprotein E knockout ascorbate anion asymmetric dimethylarginine atrial fibrillation c-Jun N-terminal kinase calmodulin carbonyl reductase cardiovascular catalases cationic amino acid transporters cationic amino acids diabetes mellitus dihydrofolate reductase dihydropteridine reductase dimethylamines dimethylarginine dimethylaminohydrolases eGFR estimated glomerular filtration rate extracellular signal-regulated kinase flavin adenine dinucleotide flavin mononucleotide forkhead protein glutathione glutathione peroxidases glutathioneperoxidase guanosine triphosphate heat shock protein hypoxia-inducible factor l-Arg l-NMMA l-NNA l-arginine leukocyte telomere length low-density lipoprotein malondialdehyde metallothionein mitogen-activated protein kinase monoamine oxidase neuronal tryptophan hydroxylase nicotinamide dinucleotide phosphate nitric oxide nuclear factor erythroid 2-related factor 2 nuclear factor κB oxidative stress peroxyredoxin phenylalanine hydroxylase protein arginine methyl transferase pterin-4a-carbinolamine dehydratase reactive nitrogen species reactive oxygen species redox factor-1 sepiapterin reductase siRNAs small interfering ribonucleic acids superoxide dismutase symmetric dimethylarginine tHcy tetrahydrobiopterin thioredoxin tocopherol total plasma homocysteine trihydrobiopterin radical tyrosine hydroxylase uric acid y+L AA y+LAT transporters α-keto-δ-(N(G),N(G)-dimethylguanidino)valeric acid

Mesh ： Animals Cardiovascular Diseases / drug therapy enzymology metabolism Enzyme Inhibitors / pharmacology therapeutic use Humans Nitric Oxide / metabolism Nitric Oxide Synthase / antagonists & inhibitors metabolism Oxidative Stress / drug effects

来  源：   DOI：10.1016/j.pharmthera.2013.07.004   PDF(Sci-hub)

Abstract：
Nitric oxide (NO) is synthetized enzymatically from l-arginine (l-Arg) by three NO synthase isoforms, iNOS, eNOS and nNOS. The synthesis of NO is selectively inhibited by guanidino-substituted analogs of l-Arg or methylarginines such as asymmetric dimethylarginine (ADMA), which results from protein degradation in cells. Many disease states, including cardiovascular diseases and diabetes, are associated with increased plasma levels of ADMA. The N-terminal catalytic domain of these NOS isoforms binds the heme prosthetic group as well as the redox cofactor, tetrahydrobiopterin (BH(4)) associated with a regulatory protein, calmodulin (CaM). The enzymatic activity of NOS depends on substrate and cofactor availability. The importance of BH(4) as a critical regulator of eNOS function suggests that BH(4) may be a rational therapeutic target in vascular disease states. BH(4) oxidation appears to be a major contributor to vascular dysfunction associated with hypertension, ischemia/reperfusion injury, diabetes and other cardiovascular diseases as it leads to the increased formation of oxygen-derived radicals due to NOS uncoupling rather than NO. Accordingly, abnormalities in vascular NO production and transport result in endothelial dysfunction leading to various cardiovascular disorders. However, some disorders including a wide range of functions in the neuronal, immune and cardiovascular system were associated with the over-production of NO. Inhibition of the enzyme should be a useful approach to treat these pathologies. Therefore, it appears that both a lack and excess of NO production in diseases can have various important pathological implications. In this context, NOS modulators (exogenous and endogenous) and their therapeutic effects are discussed.
摘要：
一氧化氮（NO）是通过三种NO合酶亚型从l-精氨酸（l-Arg）酶促合成的，iNOS,eNOS和nNOS。NO的合成被1-Arg或甲基精氨酸的胍基取代类似物如不对称二甲基精氨酸(ADMA)选择性抑制。这是细胞中蛋白质降解的结果。许多疾病状态，包括心血管疾病和糖尿病，与ADMA的血浆水平升高有关。这些NOS同工型的N端催化结构域结合血红素辅基以及氧化还原辅因子，四氢生物蝶呤（BH（4））与调节蛋白相关，钙调蛋白（CaM）。NOS的酶活性取决于底物和辅因子的可用性。BH（4）作为eNOS功能的关键调节因子的重要性表明，BH（4）可能是血管疾病状态的合理治疗靶标。BH（4）氧化似乎是与高血压相关的血管功能障碍的主要原因，缺血/再灌注损伤,糖尿病和其他心血管疾病，因为它导致由于NOS解偶联而不是NO而导致的氧衍生自由基的形成增加。因此，血管NO产生和转运的异常导致内皮功能障碍，导致各种心血管疾病。然而,一些疾病，包括神经元的各种功能，免疫和心血管系统与NO的过量产生有关。酶的抑制应该是治疗这些病症的有用方法。因此,看来，疾病中NO产生的缺乏和过量都可能具有各种重要的病理意义。在这种情况下，讨论了NOS调节剂（外源性和内源性）及其治疗效果。
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