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，雌激素的丧失加剧了这些变化。绝经后的女性会突然加速动脉粥样硬化。恢复雌激素似乎是有保护作用的；然而，关于雌激素替代使用的双盲临床研究并没有显示出好处。环氧三烯酸(EETs)是一种脂质信号分子，在血管生成、炎症反应中发挥重要作用，对缺血性损伤具有保护作用。除了前列腺素和白三烯外，EETs是花生四烯酸(AA)代谢的第三条途径。鉴于其特性，EETs有可能成为绝经后的保护性物质。可溶性环氧化物水解酶(SEH)将EETs转化为二羟基二十碳三烯酸(DHETs)，DHETs被认为是促炎的，缺乏EETs的有益特性。在先导研究中，我们发现血管sEH随着年龄的增长而增加，而左心室sEH的表达随着雌激素的替代而减少。雌激素丢失和衰老导致氧化应激增加，炎症增加，内皮祖细胞功能障碍导致血管修复受损，炎症增加，单核细胞黏附增加。我们的假设是，EETs的治疗和/或sEH抑制将阻止EETs的水解为DHETs，可以减轻与雌激素丢失和衰老相关的炎症变化。我们将以三个具体目标解决这一假说：SA 1-定义衰老和雌激素丢失对EET代谢的影响，以及EET/DHETs变化对血管功能和炎症的影响。这项计划中的工作将调查EETs随年龄的变化和雌激素状态的变化。终点将包括EETs和雌激素对血管功能的影响，EETs表达的调节，以及在使用和不使用雌激素的老年和成年挪威布朗(NB)大鼠中AA/EETs的代谢概况。SA2-确定EETs/DHETs变化与衰老和E2丢失对内皮祖细胞功能和增殖的影响。EET具有血管扩张剂、血管生成和抗炎等特性，但它们对EPC的影响尚不清楚。我们假设老年内皮祖细胞的功能受损，而使用EETs治疗会改善这种情况。计划工作的终点将包括EPC的增殖、管的形成以及归巢和伤口修复的体外和体内模型。SA3.-研究衰老与雌激素停用和EETs对单核细胞激活和黏附的影响-这些实验探索衰老与雌激素对单核细胞激活的影响，以及EETs/DHETs如何改变单核细胞的激活和黏附。计划中的研究将提供关于衰老与雌激素丢失的影响的新知识，以及EETs在缓解衰老的炎性变化中的潜在作用。 公共卫生相关性： 这项拟议的工作将研究EETs在调节炎症和血管随年龄变化方面的作用。EETs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。这项研究调查了雌激素变化和EETs之间的联系。越来越多的妇女在武装部队服役。美国有180万名女性退伍军人，占退伍军人总数的7.7%。1 2008年，退伍军人管理局为281,000名女性提供了医疗保健，比2006年增加了12%。据预测，在25年内，17%的退伍军人将是女性。女性退伍军人的年龄中值为47岁，由于更年期的平均年龄为55岁，因此有相当数量的女性退伍军人处于围绝经期或绝经期后。这项计划中的工作与退伍军人群体非常相关，因为退伍军人群体的血管疾病和心脏病的发病率很高。虽然这项工作的重点是雌激素和EETs，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.