Estrogen, Aging and Vascular Inflammation

描述（由申请人提供）： 衰老的特征是全身炎症变化和器官功能障碍。在女性中，雌激素的损失加剧了这些变化。绝经后妇女动脉粥样硬化突然加速。恢复雌激素似乎是有保护作用的;然而，关于使用雌激素替代品的双盲临床研究并没有显示出益处。环氧二十碳三烯酸（Epoxyecosatrienoic Acids，ESTs）是一种脂质信号分子，对血管生成、炎症反应和缺血性损伤具有重要的保护作用。除了花生四烯酸和白细胞三烯外，花生四烯酸（AA）代谢的第三条途径是雌二醇。考虑到它们的特性，Ehrs有可能在绝经后起到保护作用。可溶性环氧化物水解酶（sEH）将雌二醇转化为二羟基-二十碳三烯酸（DHE 3），其被认为是促炎性的并且缺乏雌二醇的有益特性。在初步研究中，我们发现血管sEH随着年龄的增长而增加，左心室sEH表达随着雌激素替代而减少。雌激素损失与衰老结合导致氧化应激增加、炎症增加、EPC功能障碍，导致血管修复受损、炎症增加和单核细胞粘附增加。我们的假设是，将阻断雌二醇水解为脱氢酶的雌二醇治疗和/或sEH抑制可以减轻与雌激素损失和衰老相关的炎症变化。我们将用三个具体目标来解决这个假设：SA 1 -定义衰老与雌激素损失对EET代谢的影响，以及EET/DHE 3的变化对血管功能和炎症的影响。计划中的工作将调查雌激素随着年龄的增长和雌激素状态的变化。终点将包括雌激素与雌激素对血管功能的影响，雌激素表达的调节，以及在有和没有雌激素的老年和成年挪威布朗（NB）大鼠中AA/雌激素的代谢特征。SA 2-确定E2/DH 3的变化相对于老化和E2损失对EPC功能和增殖的影响。内皮素具有血管扩张、血管生成和抗炎特性，但其对EPCs的作用尚不清楚。我们推测，老年EPCs将有受损的功能，这将通过EPCs治疗得到改善。计划工作的终点将包括EPC增殖、管形成以及归巢和伤口修复的体外和体内模型。SA 3. - 研究衰老与雌激素戒断和雌二醇对单核细胞活化和粘附的影响-这些实验探索了衰老与雌激素对单核细胞活化的影响，以及雌二醇/雌二醇如何改变单核细胞活化和粘附。计划中的研究将提供关于衰老与雌激素损失的影响的新知识，以及Escherichia coli在改善衰老的炎症变化中的潜在作用。 公共卫生相关性： 这项拟议的工作将研究Ehrs的作用，Ehrs是一组分子，其在体内的合成可能会随着时间的推移而变化，在调节炎症和血管老化的变化中。这项研究调查了雌激素和雌二醇变化之间的联系。越来越多的妇女在武装部队服役。美国有180万女性退伍军人，占退伍军人人口的7.7%。1 2008年，退伍军人管理局为281，000名妇女提供了医疗保健，比2006年增加了12%。预计在25年内，17%的退伍军人将是女性。女性退伍军人的平均年龄为47岁，由于绝经发生在平均55岁，因此有相当数量的女性退伍军人处于绝经期或绝经后。计划开展的工作与退伍军人群体密切相关，因为他们的血管疾病和心脏病发病率很高。虽然这项工作的重点是雌激素和雌二醇，但它将提供新的见解和潜在的新疗法（sEH抑制剂）血管疾病，这可以帮助男性和女性退伍军人。

DESCRIPTION (provided by applicant): Aging is characterized by systemic inflammatory changes and organ dysfunction. In females, loss of estrogen compounds these changes. Post-menopausal women have an abrupt acceleration of atherosclerosis. It would seem that restoration of estrogen would be protective; however, double- blind clinical studies on the use of estrogen replacement have not shown a benefit. Epoxyecosatrienoic acids (EETs), which are lipid signaling molecules, have important effects on angiogenesis, inflammation and are protective against ischemic injury. EETs represent the third pathway of arachidonic acid (AA) metabolism, in addition to prostaglandins and leukotrienes. Given their properties, EETs have the potential to be protective post-menopause. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxy-eicosatrienoic acids (DHETs), which are thought to be pro- inflammatory and to lack the beneficial properties of EETs. In pilot studies we found that vascular sEH increased with aging and that left ventricular sEH expression decreased with estrogen replacement. Estrogen loss combined with aging leads to increased oxidative stress, increased inflammation, dysfunctional EPCs leading to impaired vascular repair, increased inflammation and increased monocyte adhesion. Our hypothesis is that EETs treatment and/or sEH inhibition, which will block hydrolysis of EETs to DHETs, can mitigate the inflammatory changes associated with estrogen loss and aging. We will address this hypothesis with three specific aims: SA 1 - Define the effect of aging vs. estrogen loss on EET metabolism, and the effect of changes in EET/DHETs on vascular function and inflammation. The planned work will investigate changes in EETs with aging and changes in estrogen status. End points will include the effect of EETs vs. estrogen on vascular function, regulation of EETs expression, and the metabolic profile of AA/EETs in aged and adult Norway Brown (NB) rats with and without estrogen. SA2 - Determine the effect of changes in EETs/DHETs vs. aging and E2 loss on EPCs function and proliferation. EETs have vasodilator, angiogenic and anti-inflammatory properties, but their effect on EPCs is not known. We hypothesize that aged EPCs will have impaired function, and that this will be improved by treatment with EETs. Endpoints in the planned work will include EPC proliferation, tube formation and both in vitro and in vivo models of homing and wound repair. SA3. - Investigate the effect of aging vs. estrogen withdrawal and EETs on monocyte activation and adhesion - These experiments explore the effect of aging vs. estrogen on monocyte activation, and how EETs/DHETs modify monocyte activation and adhesion. The planned studies will provide new knowledge of the effect of aging vs. estrogen loss, and the potential role of EETs in ameliorating the inflammatory changes of aging. PUBLIC HEALTH RELEVANCE: The proposed work will investigate the role of EETs, a set of molecules whose synthesis in the body may vary over time, in modulating inflammation and changes in the blood vessels with aging. The research investigates links between changes in estrogen and EETs. An increasing number of women are serving in the armed forces. There are 1.8 million female veterans in the US, which is 7.7% of the veteran population.1 In 2008 the VA provided health care to 281,000 women, an increase of 12% over 2006. It is projected within 25 years 17% of veterans will be female. The median age of female veterans is 47, and as menopause occurs at a mean age of 55, there are a significant number of female veterans who are peri- or post-menopausal. The planned work is very relevant to the veterans' population, which has a high incidence of vascular disease as well as heart disease. Although the work focuses on estrogen and EETs, it will provide new insights and potentially new therapies (sEH inhibitors) vascular disease, which can help both male and female veterans.