Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle
Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle
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DOI：
10.1016/j.mehy.2007.01.070
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发表时间：
2007-01-01
影响因子：
4.7
通讯作者：
Pall, Martin L.
中科院分区：
文献类型：
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作者：
Pall, Martin L.
能够增加一氧化氮水平的短期压力源，会引发慢性疲劳综合征、多种化学物质敏感性、纤维肌痛和创伤后应激障碍等疾病。这些应激源主要通过一氧化氮产物过氧亚硝酸盐起作用，被认为启动了一个复杂的恶性循环机制，即一氧化氮/一氧化氮循环，导致慢性疾病。NO/ onoo循环的复杂性提出了一个问题，即开启这个循环的机制是这个复杂的循环本身，还是一个更简单的机制是主要的开关。本文提出，该开关涉及两个可变开关的组合，即一氧化氮合酶（NOS）活性的增加和NOS活性的部分解偶联，其中解偶联是由四氢生物蝶呤（BH4）缺乏引起的。NOS解偶联导致NOS酶产生超氧化物，过氧亚硝酸盐的另一前体，代替一氧化氮。因此，部分解偶联将导致NOS蛋白像过氧酸合成酶一样起作用，进而导致nf - κ B活性增加。已知过氧亚硝酸盐氧化BH4，因此部分解偶联可能引发恶性循环，随着时间的推移传播部分解偶联。高NOS活性和BH4消耗的结合将导致潜在的恶性循环，可能会开启更大的NO/ onoo循环，从而产生慢性疾病的症状和体征。过氧亚硝酸盐在NO/ onoo循环中的作用也意味着这种解偶联是慢性相循环机制的一部分，因此降低解偶联的药物将在治疗中有用。(c) 2007 Elsevier Ltd.版权所有。
Short-term stressors, capable of increasing nitric oxide levels, act to initiate cases of illnesses including chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia and posttraumatic stress disorder. These stressors, acting primarily through the nitric oxide product, peroxynitrite, are thought to initiate a complex vicious cycle mechanism, known as the NO/ONOO-cycle that is responsible for chronic illness. The complexity of the NO/ONOO-cycle raises the question as to whether the mechanism that switches on this cycle is this complex cycle itself or whether a simpler mechanism is the primary switch. It is proposed here that the switch involves a combination of two variable switches, the increase of nitric oxide synthase (NOS) activity and the partial uncoupling of the NOS activity, with uncoupling caused by a tetrahydrobiopterin (BH4) deficiency. NOS uncoupling causes the NOS enzymes to produce superoxide, the other precursor of peroxynitrite, in place of nitric oxide. Thus partial uncoupling will cause NOS proteins to act like peroxyritrite synthases, leading, in turn to increased NF-kappa B activity. Peroxynitrite is known to oxidize BH4, and consequently partial uncoupling may initiate a vicious cycle, propagating the partial uncoupling over time. The combination of high NOS activity and BH4 depletion will lead to a potential vicious cycle that may be expected to switch on the larger NO/ONOO-cycle, thus producing the symptoms and signs of chronic illness. The role of peroxynitrite in the NO/ONOO-cycle also implies that such uncoupling is part of the chronic phase cycle mechanism such that agents that lower uncoupling will be useful in treatment. (c) 2007 Elsevier Ltd. All rights reserved.