Antioxidant therapy for atherosclerotic vascular disease: the promise and the pitfalls.
Antioxidant therapy for atherosclerotic vascular disease: the promise and the pitfalls.
复制标题
动脉粥样硬化性血管疾病的抗氧化疗法：前景和陷阱。
DOI：
10.1152/ajpheart.2002.282.3.h797
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Weintraub,NealL
中科院分区：
文献类型：
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作者：
Shihabi,Ahmad;Li,Wei-Gen;MillerJr,FrancisJ;Weintraub,NealL
抗氧化剂在治疗与氧化应激相关的疾病方面的潜在价值已为科学家和临床医生所熟知，并且引起了患者的极大兴趣。氧化应激是一个术语，用于描述活性氧（ROS），如超氧阴离子（O2）和过氧化氢（H2 O2）的产生和破坏之间的不平衡，从而导致细胞和组织损伤。氧的基本性质决定了自由基的破坏力，特别是它们的高反应性。人类每天消耗250克氧气，其中3-5%转化为O2和其他活性物质（38）。ROS对细胞和细胞外靶点如膜脂质、蛋白质和DNA造成的损伤在许多病理状态下明显有助于组织和器官功能障碍。特别是，低密度脂蛋白（LDL）在血管壁中的氧化被广泛接受，在动脉粥样硬化的发病机制中发挥着重要作用（5，40，44，56）。因此，抗氧化剂在预防人类动脉粥样硬化及其并发症方面应该是有益的。事实上，观察和流行病学研究，虽然无法建立因果关系，表明增加天然抗氧化维生素的饮食摄入量与心血管疾病的风险降低（7，8，22，24，26，39，43，46）。那么，为什么抗氧化剂方案的一级和二级预防试验产生的结果并不令人鼓舞（14、21、32、37、45、51、57）？一些试验受到批评，因为抗氧化剂治疗的剂量方案或持续时间不足，抗氧化剂之间的有害相互作用，以及招募或排除患者子集的缺陷等因素。然而，这些简单的解释并不能解释所有仔细进行的试验的负面结果。缺乏抗氧化剂的证明益处，加上最近描述的对脂质代谢的有害影响（4），导致一些人认为使用补充抗氧化维生素甚至可能对正在服用降脂药物的患者有害（25）。补充抗氧化维生素预防人类动脉粥样硬化的明显缺乏功效，不仅应该引起临床医生和患者的注意，而且应该引起研究血管疾病基本机制的科学家的注意。在这方面，我们讨论了几个概念，出现了“抗氧化剂悖论”，可能提供深入了解ROS的作用，动脉粥样硬化性血管疾病的发病机制和传统的抗氧化剂治疗的陷阱。
THE POTENTIAL VALUE OF ANTIOXIDANTS in treating conditions associated with oxidative stress is well known to scientists and clinicians and is of immense interest to patients. Oxidative stress is a term used to describe an imbalance between the production and destruction of reactive oxygen species (ROS), such as superoxide anions (O2) and hydrogen peroxide (H2O2), thereby leading to cellular and tissue injury. The basic properties of oxygen are responsible for the destructive power of free radicals, in particular, their high reactivity. Humans consume 250 g of oxygen every day, and of this 3–5% is converted to O2 and other reactive species (38). The damage inflicted by ROS on cellular and extracellular targets such as membrane lipids, proteins, and DNA clearly contributes to tissue and organ dysfunction in many pathological states. In particular, the oxidation of low-density lipoproteins (LDL) in the vascular wall is widely accepted to play a fundamental role in the pathogenesis of atherosclerosis (5, 40, 44, 56). It stands to reason, then, that antioxidants should be beneficial in preventing atherosclerosis and its complications in humans. Indeed, observational and epidemiological studies, although unable to establish a cause-and-effect relationship, suggest that increased dietary intake of naturally occurring antioxidant vitamins is associated with lower risk of cardiovascular disease (7, 8, 22, 24, 26, 39, 43, 46). Why, then, have primary and secondary prevention trials of antioxidant regimens yielded less than encouraging results (14, 21, 32, 37, 45, 51, 57)? Some trials have been criticized because of insufficient dosing regimens or durations of antioxidant therapy, harmful interactions between the antioxidant agents, and flaws in enrolling or excluding subsets of patients, among other factors. Nevertheless, these simple explanations do not explain the negative results of all carefully conducted trials. The lack of proven benefit of antioxidants, in conjunction with a recently described detrimental effect on lipid metabolism (4), has led some to suggest that the use of supplemental antioxidant vitamins could even be hazardous to patients who are taking lipid-lowering medications (25). The apparent lack of efficacy of supplemental antioxidant vitamins to prevent atherosclerosis in humans should be noteworthy not only to clinicians and patients but also to scientists who study the basic mechanisms of vascular disease. In this regard, we discuss several concepts that have emerged from the “antioxidant paradox” that might provide insight into the role of ROS in the pathogenesis of atherosclerotic vascular disease and into the pitfalls of conventional antioxidant therapy.