Coronary Reactivity and Thromboxane Receptor Expression

冠状动脉反应性和血栓素受体表达

• 批准号: 6334121
• 负责人: R Kent HERMSMEYER
• 金额: $ 39.25万
• 依托单位: DIMERA, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334121
• 关键词: Macaca mulatta; calcium flux; coronary artery; dihydrotestosterone; estrogens; female; hormone receptor; hormone regulation /control mechanism; ovariectomy; pathologic process; postmenopause; progesterone; prostaglandin receptor; protein kinase C; receptor expression; sex hormones; thromboxanes; vasomotion

DESCRIPTION (Verbatim from the application): Coronary artery reactivity modulation is a rarely recognized, but important, consequence of gonadal steroid actions on blood vessels of primates, and thus this factor has profound significance for aging in menopausal women. This project addresses coronary hyperreactivity as an aspect of increased heart disease that is relatively overlooked. The major increase in risk of heart disease with age in women during menopause is strongly correlated with falling levels of estrogens (E), and more profoundly of progesterone (P), in the presence of continued non-ovarian E and testosterone (T) production. The androgen path, particularly dihydrotestosterone (DHT), appears to be important. The imbalance of E & P & T, the 3 ovarian steroids, is hypothesized to lead to loss of a protected state. Previously, we showed that return of even subphysiological levels of estrogen and progesterone restores normal coronary reactivity in ovariectomized primates. In this project, surgically menopausal monkeys will be treated for 2 weeks with E and/or P with controlled levels of DHT, or with 2 week increases or decreases in DHT during controlled E and P, to further probe the coronary roles of these 3 steroid hormones and their balance. E, P, and DHT appear to physiologically regulate coronary reactivity and thromboxane A2 (TxA2) receptors. DHT, the most potent known inducer of TxA2 receptors is formed locally in coronary arteries, more than is E from 1, when there is a deficiency of P. Without P, the balance favors conversion of T to DHT rather than to E. P also directly suppresses TxA2 receptor expression. Less than threshold P is thus hypothesized to be a triple adverse influence. Studies of E, P, and TxA2 receptor distribution in the coronary artery wall by immunocytochemistry, TxA2 receptor binding by Scatchard analysis, blood levels of E, P, and DHT, coronary diameter, blood pressure, and cellular studies of Ca2+ and protein kinase C will be made to probe these pathophysiological mechanisms of coronary hyperreactivity with multiple manipulations of E, P, and DHT. In vivo catheterization laboratory studies will be combined with gross and histopathological examination of coronary arteries to determine correlations with hyperreactivity and TxA2 receptor expression. Tests of E, P, and DHT effects on cellular factors underlying vasodilator and vasoconstrictor changes in primate coronary arteries are important for understanding how to protect against coronary artery risks during the post-menopausal aging process.

描述（来自应用程序的逐字描述）：冠状动脉反应性 调节是一种很少被认识到的，但重要的， 类固醇对灵长类动物血管的作用，因此这一因素具有深远的意义。 更年期妇女衰老的意义。该项目旨在解决冠状动脉 高反应性是心脏病增加的一个方面， 忽视女性心脏病风险随着年龄的增长而大幅增加 在绝经期间与雌激素（E）水平下降密切相关， 孕激素（P），在持续存在的 非卵巢E和睾酮（T）的产生。雄激素途径，特别是 二氢睾酮（DHT），似乎是重要的。E & P & T的不平衡， 3种卵巢类固醇被假设导致保护状态的丧失。 此前，我们表明，即使是亚生理水平的雌激素恢复， 孕酮可以恢复卵巢切除后正常的冠状动脉反应性， 灵长类动物在这个项目中，手术绝经的猴子将接受2 使用E和/或P并控制DHT水平，或增加2周 或在控制E和P期间减少DHT，以进一步探测冠状动脉 这三种类固醇激素的作用及其平衡。E、P和DHT似乎 生理调节冠状动脉反应性和血栓素A2（TxA 2） 受体。DHT是已知最有效的TxA 2受体诱导剂， 在冠状动脉局部，当存在不足时， 没有P，平衡有利于T转化为DHT而不是E。P 还直接抑制TxA 2受体表达。小于阈值P是 因此被假设为三重不利影响。E、P和TxA 2的研究 免疫细胞化学法观察TxA 2受体在冠状动脉壁的分布 Scatchard分析受体结合，E，P和DHT的血液水平，冠状动脉 直径、血压以及Ca 2+和蛋白激酶C的细胞研究 探讨冠状动脉病变的病理生理机制 高反应性与E、P和DHT的多次操作。体内 导管插入实验室研究将与大体和 冠状动脉的组织病理学检查以确定相关性 高反应性和TxA 2受体表达。E、P和DHT测试 对血管舒张和血管收缩变化的细胞因子的影响 冠状动脉对于了解如何保护 预防绝经后衰老过程中的冠状动脉风险。