Estrogen, Aging and Vascular Inflammation

雌激素、衰老和血管炎症

• 批准号: 8245584
• 负责人: ANNE A KNOWLTON
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245584
• 关键词: Acceleration; Acids; Address; Adhesions; Adult; Age; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Arteries; Atherosclerosis; Blood Vessels; Cell Adhesion Molecules; Cell Aging; Cell Proliferation; Cell physiology; Cells; Cellular biology; Clinical Research; Clinical Trials; Development; Diabetes Mellitus; Disease; Double-Blind Method; Eicosatrienoic Acid; Endothelial Cells; Endothelium; Enzymes; Epoxide hydrolase; Estrogen Replacements; Estrogens; Exercise; Female; Functional disorder; Healthcare; Heart Diseases; Homing; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Impairment; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Injury; Knowledge; Lead; Left; Leukotrienes; Link; Lipids; Maintenance; Menopause; Metabolic; Metabolism; Methods; Microfluidics; Modeling; Molecular; Norway; Organ; Ovariectomy; Oxidative Stress; Pathway interactions; Pilot Projects; Population; Postmenopause; Process; Property; Prostaglandins; Proteins; Rattus; Regulation; Research; Role; Signaling Molecule; Stem cells; Stimulus; Testing; Time; Tissues; Tube; Vascular Diseases; Vascular System; Vasodilator Agents; Ventricular; Veterans; Withdrawal; Woman; Work; Wound Healing; age effect; age related; aged; angiogenesis; arm; base; improved; in vivo Model; inhibitor/antagonist; insight; male; metabolomics; mimetics; monocyte; public health relevance; repaired; research study; response; restoration; tissue repair; vascular inflammation

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.

描述（由申请人提供）： 衰老的特点是全身炎症变化和器官功能障碍。对于女性来说，雌激素的丧失会加剧这些变化。绝经后妇女的动脉粥样硬化急剧加速。恢复雌激素似乎具有保护作用；然而，关于使用雌激素替代品的双盲临床研究尚未显示出益处。环氧二十碳三烯酸 (EET) 是一种脂质信号分子，对血管生成、炎症具有重要作用，并可预防缺血性损伤。 EET 是除前列腺素和白三烯之外的花生四烯酸 (AA) 代谢的第三条途径。鉴于 EET 的特性，它有可能对绝经后起到保护作用。可溶性环氧化物水解酶 (sEH) 将 EET 转化为二羟基二十碳三烯酸 (DHET)，二羟基二十碳三烯酸 (DHET) 被认为具有促炎作用，并且缺乏 EET 的有益特性。在初步研究中，我们发现血管 sEH 随着衰老而增加，而左心室 sEH 表达随着雌激素替代而减少。雌激素流失与衰老相结合会导致氧化应激增加、炎症增加、EPC 功能失调导致血管修复受损、炎症增加和单核细胞粘附增加。我们的假设是，EET 治疗和/或 sEH 抑制会阻止 EET 水解为 DHET，从而减轻与雌激素流失和衰老相关的炎症变化。我们将通过三个具体目标来解决这一假设： SA 1 - 定义衰老与雌激素损失对 EET 代谢的影响，以及 EET/DHET 变化对血管功能和炎症的影响。计划的工作将调查 EET 随衰老和雌激素状态变化的变化。终点将包括 EET 与雌激素对血管功能的影响、EET 表达的调节以及有或没有雌激素的老年和成年挪威棕色 (NB) 大鼠中 AA/EET 的代谢特征。 SA2 - 确定 EET/DHET 变化与衰老和 E2 损失对 EPC 功能和增殖的影响。 EET 具有血管扩张、血管生成和抗炎特性，但其对 EPC 的影响尚不清楚。我们假设老化的 EPC 的功能会受损，而这种情况可以通过 EET 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。 SA3。 - 研究衰老与雌激素撤退和 EET 对单核细胞激活和粘附的影响 - 这些实验探讨衰老与雌激素对单核细胞激活的影响，以及 EET/DHET 如何改变单核细胞激活和粘附。计划中的研究将提供关于衰老与雌激素流失的影响以及 EET 在改善衰老炎症变化中的潜在作用的新知识。 公共卫生相关性： 拟议的工作将研究 EET 的作用，EET 是一组分子，其在体内的合成可能随时间而变化，在调节炎症和血管随衰老而变化方面的作用。该研究调查了雌激素变化和 EET 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 名女性提供医疗保健，比 2006 年增加了 12%。预计 25 年内，17% 的退伍军人将获得医疗保健服务。是女性。女性退伍军人的平均年龄为 47 岁，由于绝经期的平均年龄为 55 岁，因此有大量女性退伍军人处于绝经期或绝经后。这项计划的工作与退伍军人群体非常相关，因为退伍军人群体是血管疾病和心脏病的高发人群。尽管这项工作的重点是雌激素和 EET，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。