Atherosclerosis Stage, Estrogen Receptors, and Vascular Responses to Estrogen

动脉粥样硬化阶段、雌激素受体和血管对雌激素的反应

• 批准号: 7879995
• 负责人: THOMAS COSTIN REGISTER
• 金额: $ 29.44万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879995
• 关键词: Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Arterial Fatty Streak; Arteries; Atherosclerosis; Biochemical; Biopsy; Blood Vessels; California; Cardiovascular system; Characteristics; Clinical Trials; Companions; Complement; Complex; Coronary Arteriosclerosis; Coronary artery; Coronary heart disease; Data; Development; Disease Outcome; Early treatment; Effectiveness; Endothelial Cells; Estradiol; Estrogen Receptors; Estrogen Replacements; Estrogens; Event; Female; Foam Cells; Functional disorder; Funding; Gene Expression; Grant; Hand; Histologic; Hot flushes; Inflammatory; Inflammatory Response; Institutes; Intervention Trial; Laboratories; Length; Lesion; Lesion by Morphology; Macaca fascicularis; Measures; Mediator of activation protein; Medicine; Menopausal Symptom; Menopause; Methods; Molecular; Monkeys; Monocyte Chemoattractant Protein-1; Myocardial Infarction; Necrosis; Operative Surgical Procedures; Outcome; Postmenopause; Property; Public Health; Research; Research Personnel; Risk; Role; Smooth Muscle Myocytes; Staging; Stroke; T-Lymphocyte; Time; Universities; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; Woman; adverse outcome; atherogenesis; atheroprotective; calcification; cardiovascular risk factor; experience; iliac artery; macrophage; migration; monocyte; nonhuman primate; plaque lesion; programs; receptor expression; response

DESCRIPTION: Few, if any, issues in medicine have been more controversial than whether postmenopausal estrogen replacement (E) provides cardiovascular benefits. Much of the speculation concerns the impact of timing of postmenopausal estrogen treatment on coronary heart disease outcomes. Studies in our laboratories indicate that the stage of atherosclerosis and/or time while postmenopausal at initiation of treatment is a critical determinant of the ability of E to favorably affect arterial wall pathophysiology. E has its greatest atheroinhibitory effects in nonhuman primates early in atherosclerosis development (i.e., with coronary artery fatty streaks or initial fatty plaques), whereas with advanced atherosclerotic plaques, traditional E has few beneficial effects. Findings from our monkey studies were important in Dr. Howard Hodis1 decision to plan and initiate the Early versus Late Intervention Trial with Estradiol (ELITE), now funded by the National Institute of Aging (Grant #5R01AG024154). The proposed research is a companion study to ELITE, enabling us to conduct studies impossible to do in women, which will complement and enhance the interpretation of the ELITE data. Differential responses to E may relate to loss of vascular estrogen receptor (ER) expression in late menopause (advanced lesions), and we have observed an inverse relationship between atherosclerosis extent and ER expression in postmenopausal monkeys. We propose that atheroprotective effects of E will be dependent on the level of expression of arterial ER prior to treatment, which can be measured in monkeys but not in women. Furthermore, we propose E will have considerably different effects in advanced lesions (plaques) developed while menopausal for years compared to early lesions (fatty streaks) produced over a short menopausal period. Our approach will be to utilize histologic, immunohistologic, biochemical, and quantitative molecular methods to explore ER expression and mechanisms underlying differential effects of E (17li estradiol) on arterial biologic endpoints including lesion morphology and gene expression in surgically postmenopausal monkeys with short and long postmenopausal period before treatment (early vs. late stage atherosclerosis). The results will increase our understanding of the effects of estrogen treatment on the progression of atherosclerosis in early and late menopause, an issue of critical public health significance for women experiencing hot flushes and other menopausal symptoms faced with decisions on how to ease these problems safely without increasing the risk of adverse outcomes, such as stroke or myocardial infarction.

描述：在医学界，很少有比绝经后雌激素替代（E）是否能带来心血管益处更具争议性的问题了。许多猜测涉及绝经后雌激素治疗时机对冠心病结局的影响。我们实验室的研究表明，动脉粥样硬化的阶段和/或开始治疗时绝经后的时间是 E 有利影响动脉壁病理生理学能力的关键决定因素。 E 在非人类灵长类动物的动脉粥样硬化发展早期（即冠状动脉脂肪条纹或初始脂肪斑块）中具有最大的动脉粥样硬化抑制作用，而对于晚期动脉粥样硬化斑块，传统 E 几乎没有有益作用。我们的猴子研究结果对于霍华德·霍迪斯 (Howard Hodis) 博士决定计划和启动雌二醇早期与晚期干预试验 (ELITE) 非常重要，该试验目前由国家衰老研究所资助（拨款 #5R01AG024154）。拟议的研究是 ELITE 的配套研究，使我们能够进行在女性中不可能进行的研究，这将补充和增强对 ELITE 数据的解释。对 E 的不同反应可能与绝经后期（晚期病变）血管雌激素受体（ER）表达的丧失有关，并且我们观察到绝经后猴子的动脉粥样硬化程度与 ER 表达之间呈负相关。我们认为 E 的动脉粥样硬化保护作用将取决于治疗前动脉 ER 的表达水平，该水平可以在猴子中测量，但不能在女性中测量。此外，我们认为，与绝经期较短期间产生的早期病变（脂肪纹）相比，E 对绝经多年期间形成的晚期病变（斑块）具有显着不同的影响。我们的方法将是利用组织学、免疫组织学、生物化学和定量分子方法来探索 ER 表达和 E（17li 雌二醇）对动脉生物学终点（包括手术绝经后猴子的病变形态和基因表达）差异影响的机制（短绝经后和长绝经后）治疗前的时期（早期与晚期动脉粥样硬化）。这些结果将加深我们对雌激素治疗对绝经早期和晚期动脉粥样硬化进展的影响的了解，对于经历潮热和其他更年期症状的女性来说，这是一个具有重要公共卫生意义的问题，她们面临着如何安全地缓解这些问题的决定增加不良后果的风险，例如中风或心肌梗塞。