ESTERIFICATION OF ESTROGENS AND LIPID PEROXIDATION

说明(摘自申请者的摘要)：雌激素是 具有许多有益心血管作用的心脏保护剂。一 不寻常的作用是直接在体外低密度抗氧化保护 脂蛋白(LDL)。氧化低密度脂蛋白是一种已知的致动脉粥样硬化物质，但低密度脂蛋白具有保护作用 在体外，需要一定浓度的雌激素。因为这已经超过了1000 乘以血液中的浓度，这种作用通常被认为是 在生物学上是不相关的。最近，这种观点受到了质疑，因为它已经 已经表明，从先前孵化的血浆中分离出的低密度脂蛋白 在体外，生理浓度的雌二醇(E_2)可被保护 氧化。这种敏感性的增加是由卵磷脂：胆固醇引起的 E_2的酰基转移酶(LCAT)酯化。酰基转移酶产生一种 E2的脂肪酸酯家族，雌二醇的脂类衍生物(LE2)， 已知在低浓度的女性血液中循环。我们建议 研究雌激素及其代谢物对低密度脂蛋白保护作用的假设 通过LCAT酯化反应调节。人们对LCAT知之甚少 类固醇的酯化，尤指雌激素的酯化我们将调查 决定是否有其他类固醇底物的结构要求 雌激素，包括代谢物，特别是非活性雌激素，被酯化。 因此，产生了有效的抗氧化剂；以及其他类固醇是否可以调节 低密度脂蛋白通过抑制雌二醇的酯化而氧化。模型系统将是 研究评估LE2的抗氧化机制。我们将设计和 合成非雌激素性烷基取代苯酚 LCAT和低密度脂蛋白氧化的抑制剂。我们将确定外源的 雌二醇酯可以揭示低密度脂蛋白的氧化抵抗与性别或 更年期状态；雌激素是否能提供敏感的抗氧化剂 以低密度脂蛋白受体缺失和LCAT缺失小鼠为模型进行体内保护。这个 LCAT酯化雌激素的抗氧化作用阐明其生理作用 和一种新的雌激素效应。这些实验将有助于深入了解 一种以前未知的雌激素的非基因组作用，并提供了新的 治疗心血管疾病的药物。

DESCRIPTION (adapted from the applicant's abstract): Estrogens are cardioprotective agents with many beneficial cardiovascular effects. One unusual action is the direct in vitro antioxidant protection of low-density lipoprotein (LDL). Oxidized LDL is a known atherogenic agent but LDL protection in vitro requires uM concentrations of estrogens. Since this is over 1,000 times the concentration in blood, this action is usually considered to be biologically irrelevant. Recently, this view has been questioned because it has been shown that the LDL isolated from plasma that has been previously incubated in vitro with physiological concentrations of estradiol (E2) is protected from oxidation. This increased sensitivity is caused by lecithin: cholesterol acyltransferase (LCAT) esterification of E2. The acyltransferase produces a family of fatty acid esters of E2, lipoidal derivatives of estradiol (LE2), known to circulate in female blood in low concentration. We propose to investigate the hypothesis that LDL protection, by E2 and its metabolites, is regulated through LCAT esterification. Very little is known about the LCAT esterification of steroids, especially estrogens. We will investigate the structural requirements for steroid substrates to determine whether other estrogens, including metabolites, especially inactive estrogens, are esterified thus, producing potent antioxidants; and whether other steroids can regulate LDL oxidation by inhibiting the esterification of E2. Model systems will be studied to assess the antioxidant mechanism of LE2. We will design and synthesize non-estrogenic alkylhydroxy substituted phenols as substrates for LCAT and inhibitors of LDL oxidation. We will determine whether exogenous E2-esters can uncover an oxidative resistance of LDL related to gender or menopausal status; whether estrogen-esters can provide sensitive antioxidant protection in vivo using LDL receptor-null and LCAT-null mice as models. The antioxidant action of LCAT esterified estrogens illuminates their physiology and a novel estrogenic effect. These experiments will contribute insights into a previously unknown non-genomic action of estrogens and provide new therapeutic agents for cardiovascular disease.