EFFECTS OF ESTROGENS AND PROGESTINS ON ATHEROGENESIS

本申请中提出的培训和研究将得到赞助 由亚当斯博士主持，并将在动脉硬化研究中进行 中心和比较医学临床研究中心。 博士 瓦格纳正在寻求SERCA的支持，以进一步发展她作为一个 独立调查员，特别强调心血管健康 老年女性 这些研究将利用一种特征良好的灵长类动物 模型，雌性食蟹猴，它喜欢女人在大多数西方 严重程度较轻的动脉粥样硬化性冠心病 (CHD)而不是男性 致病机制 在女性中研究动脉粥样硬化是困难的，因为动脉粥样硬化 经过多年的缓慢发展。虽然CHD是 美国妇女发病率和死亡率的主要原因，临床 事件相对不频繁地发生。基于这些原因，我们建议 利用灵长类动物模型来研究性激素缺乏的影响， 性激素替代和口服避孕药治疗 动脉粥样硬化的发病机制。 对人类和非人类灵长类动物的研究发现， 雌激素的部分有益作用可归因于 血浆脂蛋白风险变量的变化。 这表明 雌激素可通过与动脉粥样硬化的形成直接相互作用， 动脉壁或通过改变血浆成分， 脂蛋白 这项研究将探索分子和细胞 雌激素和孕激素的作用机制。 的影响 将研究性类固醇对以下参数的影响：1） 早期动脉粥样硬化形成的功能参数，内皮 通过动脉LDL摄取和降解确定的功能障碍， 单核细胞粘附于内皮细胞和内膜细胞增殖，2） 全身和肝脏LSL代谢，3）血浆HDL组成及其 胆固醇逆向转运功能，4）细胞因子表达 和生长因子，以及5）动脉粥样硬化相关 血管反应受损。 如果如怀疑的那样， 这将为预防性或 这些类固醇在CHD中的治疗用途。

The training and research proposed in this application will be sponsored by Dr. Adams and will take place in both the Arteriosclerosis Research Center and the Comparative Medicine Clinical Research Center. Dr. Wagner is seeking SERCA support to further her development as an independent investigator with special emphasis on cardiovascular health of aging females. The studies will utilize a well characterized primate model, the female cynomolgus monkey, which like women in most Western societies, develops less severe atherosclerotic coronary heart disease (CHD) than its male counterpart. Pathogenetic mechanisms of atherogenesis are difficult to study in women, since atherosclerosis develops slowly over a period of many years. Also, while CHD is the leading cause of morbidity and mortality in American women, clinical events occur relatively infrequently. For these reasons we propose to utilize a primate model to study the effect of sex hormone deficiency, sex hormone replacement and oral contraceptive treatment on the pathogenesis of atherosclerosis. Studies of both human and nonhuman primates have found that only a portion of the beneficial effects of estrogens can be attributed to changes in plasma lipoprotein risk variables. This suggests that estrogens may retard atherogenesis by interacting by either directly at the arterial wall or by modifying plasma components in addition to lipoproteins. The studies proposed will explore molecular and cellular mechanisms by which estrogens and progestins may be acting. The effects of sex steroids on the following parameters will be investigated: 1) functional parameters of early atherogenesis eg., endothelial dysfunction as determined by arterial LDL uptake and degradation, monocyte adhesion to the endothelium, and intimal cell proliferation, 2) whole body and hepatic LSL metabolism, 3) plasma HDL composition and its function in reverse cholesterol transport, 4) expression of cytokines and growth factors by arterial cells, and 5) atherosclerosis-related impairment of vascular responses. If, as suspected, beneficial effects are found, this would provide a rational basis for the prophylactic or therapeutic use of these steroids in CHD.