ESTROGENS AND LIPOPROTEIN OXIDATION

雌激素和脂蛋白氧化

• 批准号: 2735289
• 负责人: CAROLE Lynn BANKA
• 金额: $ 25.97万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2735289
• 关键词: antiatherogenic agent; antioxidants; apolipoproteins; atherosclerosis; chelating agents; chemical structure function; cholesterol; disease /disorder model; esterification; estradiol; estrogens; female; high density lipoproteins; hormone regulation /control mechanism; human tissue; laboratory mouse; low density lipoprotein; low density lipoprotein receptor; monoclonal antibody; ovariectomy; oxidation; oxidative stress; peroxidation; radioimmunoassay

Estrogens protect against heart disease. This protection has been attributed to estrogen-mediated beneficial changes in plasma lipoprotein levels. Recent data has clearly shown estrogen-mediated inhibition of atherogenesis in the absence of lipoprotein changes, suggesting other important mechanisms of estrogen protection. I hypothesize that estrogens inhibit atherogenesis in part by selectively protecting high density lipoprotein (HDL) from deleterious oxidation. Oxidation of HDL is known to compromise its role in reverse cholesterol transport, thereby reducing its protective effects. Oxidation is predicted to render HDL less able to protect low density lipoprotein (LDL) from oxidation and to increase the catabolic rate for HDL. The prospect that estrogens protect HDL from damage that compromises its functions or accelerates its clearance adds a new dimension to our understanding of HDL protection in women. This proposal will test the following hypothesis: 1) a direct relationship exists between estrogen-mediated antioxidant protection of HDL and decreased atherogenesis in vivo; 2) antioxidant effects and hormonal effects of estradiol can be dissociated by structural alteration of the steroid; 3) estrogens selectively protect HDL from oxidation; and 4) selective estrogen protection of HDL results from HDL-mediated esterification of estrogens. Comparison of the structure/antioxidant activity relationship for a panel of estrogens will identify the most effective naturally occurring estrogenic antioxidants for HDL. In addition, it will establish the key structural requirements of a potent antioxidant. This could lead to the design of a steroid antioxidant that does not bind receptor and, therefore, has no feminizing activity. Such a drug will be suitable for use in men. The potential for an antioxidant that could be administered by transdermal patch is evident. In addition, I will define the most potent antioxidant of the receptor-active estrogens, information useful for estrogen replacement therapy in postmenopausal women. Elucidating the mechanism of the selective estrogen protection of HDL will add to our understanding of this complex lipoprotein. The information gained through testing these hypotheses will enhance our knowledge of the atheroprotective effects of estrogen.

雌激素可以预防心脏病。 这种保护已 归因于雌激素介导的血浆脂蛋白的有益变化 水平。 最近的数据清楚地表明雌激素介导的抑制作用 在没有脂蛋白变化的情况下发生动脉粥样硬化，这表明其他 雌激素保护的重要机制。 我假设 雌激素部分通过选择性保护高浓度来抑制动脉粥样硬化 来自有害氧化的密度脂蛋白（HDL）。 高密度脂蛋白的氧化 已知会损害其在逆转胆固醇转运中的作用，从而 降低其保护作用。 预计氧化会产生 HDL 保护低密度脂蛋白 (LDL) 免受氧化的能力较差， 增加 HDL 的分解代谢率。雌激素保护的前景 HDL 免受损害，从而损害其功能或加速其功能 间隙为我们对 HDL 保护的理解增加了一个新的维度 女性。 该提案将检验以下假设：1）直接 雌激素介导的抗氧化保护之间存在关系 HDL 和减少体内动脉粥样硬化形成； 2）抗氧化作用和 雌二醇的荷尔蒙效应可以通过结构改变来消除 类固醇； 3）雌激素选择性保护HDL不被氧化；和 4）雌激素对HDL的选择性保护是HDL介导的结果 雌激素的酯化作用。结构/抗氧化剂比较 一组雌激素的活性关系将确定最 对 HDL 有效的天然雌激素抗氧化剂。 在 此外，它将确定有效的关键结构要求 抗氧化剂。 这可能导致类固醇抗氧化剂的设计 不结合受体，因此不具有女性化活性。 这样的 一种药物将适合男性使用。抗氧化剂的潜力 可以通过透皮贴剂施用的这一点是显而易见的。 此外， 我将定义受体活性最强的抗氧化剂 雌激素，对雌激素替代疗法有用的信息 绝经后妇女。 阐明选择性机制 雌激素对 HDL 的保护将增加我们对这种复合物的理解 脂蛋白。 通过检验这些假设获得的信息 将增强我们对雌激素的动脉粥样硬化保护作用的了解。