SUPPRESSING NADPH OXIDASE-DEPENDENT OXIDATIVE STRESS IN THE VASCULATURE WITH NITRIC OXIDE DONORS
SUPPRESSING NADPH OXIDASE-DEPENDENT OXIDATIVE STRESS IN THE VASCULATURE WITH NITRIC OXIDE DONORS
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DOI：
10.1111/j.1440-1681.2008.05055.x
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发表时间：
2008-11-01
影响因子：
2.9
通讯作者：
Selemidis, Stavros
中科院分区：
文献类型：
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作者：
Selemidis, Stavros
1. 血管中产生的活性氧，包括超氧阴离子，有助于心血管疾病状态的发病机制，如动脉粥样硬化。超氧化物的一个重要来源是血管NADPH氧化酶，该酶的上调导致动脉粥样硬化的氧化应激。动脉中过量的超氧化物直接使内皮源性一氧化氮（NO）失活，损害其血管保护作用。鉴于一氧化氮生物利用度的降低是动脉粥样硬化病理生理的关键，外源性一氧化氮供体替代一氧化氮可能会恢复疾病期间一氧化氮的不足。虽然一氧化氮供体的有机硝酸盐家族通常是动脉粥样硬化和心绞痛症状急性治疗的首选，但这类化合物中的大多数不适合长期治疗，因为它们通过激活和上调血管NADPH氧化酶引起氧化应激，诱导对随后的硝酸盐治疗和内源性一氧化氮的耐受性。硝酸盐的这些问题不仅限制了它们的治疗利用，而且也抑制了对新一代NO供体的兴趣。最近的证据表明，与有机硝酸盐形成鲜明对比的是，较新年龄的二氮二酸NONOate类NO供体抑制血管NADPH氧化酶依赖的超氧化物产生，并且不太可能诱导耐受性，使其更适合抑制动脉粥样硬化中的氧化应激。在这里，我们假设NONOates提供了一种抑制NADPH氧化酶依赖的氧化应激的新方法，以恢复血管NO水平，从而预防甚至逆转动脉粥样硬化。
1. Reactive oxygen species produced in the vasculature, including superoxide anion, contribute to the pathogenesis of cardiovascular disease states, such as atherosclerosis. A critical source of superoxide is vascular NADPH oxidase and upregulation of this enzyme brings about the oxidative stress underlying atherosclerosis. Excessive superoxide in arteries directly inactivates endothelium-derived nitric oxide (NO), compromising its vasoprotective effects.2. Given that a reduction in NO bioavailability is key in the pathophysiology of atherosclerosis, replacement of NO by exogenously administered NO donors may restore the deficit in NO during disease. Although the organic nitrate family of NO donors is often the first choice for the acute management of symptoms of atherosclerosis and angina pectoris, most of the compounds in this class are unsuitable for long-term therapy because they cause oxidative stress by activation and upregulation of vascular NADPH oxidase and induce tolerance to subsequent nitrate treatment and endogenous NO. These problems of nitrates have not only limited their therapeutic exploitation, but have also stifled interest in newer-generation NO donors.3. Recent evidence indicates that, in stark contrast with the organic nitrates, the newer-age diazeniumdiolate NONOate class of NO donors suppress vascular NADPH oxidase-dependent superoxide production and are less likely to induce tolerance, making them more suitable for suppression of oxidative stress in atherosclerosis.4. Here, it is hypothesized that NONOates provide a novel means of suppressing NADPH oxidase-dependent oxidative stress to restore vascular NO levels to prevent, and even reverse, atherosclerosis.