ESTERIFICATION OF ESTROGENS AND LIPID PEROXIDATION

描述（改编自申请人的摘要）：雌激素是 具有许多有益的心血管作用的心脏保护剂。一 不同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LDL是一种已知的致动脉粥样硬化剂，但LDL保护 需要uM浓度的雌激素。因为这是超过1000 倍的浓度在血液中，这种行动通常被认为是 与生物学无关最近，这一观点受到质疑，因为它已与 已经表明，从先前孵育过的血浆中分离的LDL 在体外用生理浓度的雌二醇（E2）保护， 氧化这种增加的敏感性是由卵磷脂引起的：胆固醇 酰基转移酶（LCAT）酯化E2。酰基转移酶产生 E2的脂肪酸酯家族，雌二醇（LE 2）的类脂衍生物， 已知在女性血液中循环的浓度很低。我们建议 研究E2及其代谢产物对LDL的保护作用， 通过LCAT酯化进行调节。对LCAT知之甚少 类固醇，尤其是雌激素的酯化作用。我们将调查 类固醇底物的结构要求，以确定其他 雌激素，包括代谢物，特别是非活性雌激素， 因此，产生有效的抗氧化剂;以及其他类固醇是否可以调节 通过抑制E2的酯化来氧化LDL。模型系统将 研究以评估LE 2的抗氧化机制。我们将设计和 合成非雌激素烷基羟基取代酚作为底物， LCAT和LDL氧化抑制剂。我们将确定是否外源性 E2-酯可以揭示与性别或性别相关的LDL的氧化抗性。 绝经状态;雌激素酯是否能提供敏感的抗氧化剂 使用LDL受体缺失和LCAT缺失小鼠作为模型进行体内保护。的 LCAT酯化雌激素的抗氧化作用阐明了它们的生理 和新的雌激素作用。这些实验将有助于深入了解 以前未知的雌激素的非基因组作用，并提供新的 用于心血管疾病的治疗剂。

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.