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）： 衰老的特征是全身性炎症变化和器官功能障碍。在女性中，雌激素的丧失使这些变化化合物。绝经后妇女突然加速了动脉粥样硬化。雌激素的恢复似乎是保护性的。但是，关于雌激素替代的使用双盲临床研究尚未显示出好处。脂质信号分子的环氧心钠酸（EET）对血管生成，炎症具有重要作用，并保护性缺血性损伤。除了前列腺素和白细胞外，EET代表了花生四烯酸（AA）代谢的第三个途径。鉴于它们的特性，EET有可能成为绝经后的保护性。可溶性环氧化物水解酶（SEH）将EET转换为二羟基环酸二烯酸（DHETS），被认为是炎性炎性的，并且缺乏EET的有益特性。在试点研究中，我们发现血管SEH随着衰老而增加，左心室SEH表达随雌激素替代而降低。雌激素流失与衰老相结合会导致氧化应激增加，炎症增加，功能失调的EPC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的治疗和/或SEH抑制作用将阻止EET的水解为DHET，可以减轻与雌激素丧失和衰老有关的炎症变化。我们将以三个特定的目的解决这一假设：SA 1-定义衰老与雌激素丧失对EET代谢的影响，以及EET/DHETS变化对血管功能和炎症的影响。计划的工作将调查随着衰老状态的衰老和雌激素状况变化的EET的变化。终点将包括Eets与雌激素对血管功能的影响，EET表达的调节以及具有和不具有雌激素的老年和成年挪威棕色（NB）大鼠的AA/EET的代谢谱。 SA2-确定EET/DHETS与老化和E2损失对EPCS功能和增殖的影响。 EET具有血管扩张剂，血管生成和抗炎特性，但它们对EPC的影响尚不清楚。我们假设老化的EPC将受损功能，并且通过用EET的治疗来改善这一功能。计划工作的终点将包括EPC增殖，管形成以及体外和体内归纳和伤口修复模型。 SA3。 - 研究衰老与雌激素的戒断和EET对单核细胞激活和粘附的影响 - 这些实验探讨了衰老与雌激素对单核细胞激活的影响，以及EET/DHETS如何改变单核细胞的激活和粘附。计划的研究将为衰老与雌激素丧失的影响以及EET在改善衰老的炎症变化中的潜在作用提供新的知识。 公共卫生相关性： 拟议的工作将研究EET的作用，Eets的作用是一组分子，其在体内的合成可能会随着时间而变化，在调节炎症和血管变化随着衰老而变化。该研究研究了雌激素和EET的变化之间的联系。越来越多的妇女在武装部队中服役。美国有180万女退伍军人，占退伍军人人口的7.7％。12008年，VA为281,000名妇女提供了医疗保健，2006年增长了12％。预计，在25年内，17％的退伍军人将成为女性。女性退伍军人的中位年龄为47岁，而更年期的平均年龄为55岁，有大量的女性退伍军人是杂期或绝经后。计划的工作与退伍军人人口非常相关，退伍军人的血管疾病和心脏病的发生率很高。尽管这项工作的重点是雌激素和EET，但它将提供新的见解，并可能提供新的疗法（SEH抑制剂）血管疾病，这可以帮助男性和女性退伍军人。