Coronary Reactivity and Thromboxane Receptor Expression

冠状动脉反应性和血栓素受体表达

• 批准号: 6795355
• 负责人: R Kent HERMSMEYER
• 金额: $ 35.33万
• 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/6795355
• 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（申请中的逐字记录）：冠状动脉反应性 调节是性腺的一个很少被认识到但很重要的结果 类固醇对灵长类动物血管的作用，因此该因素具有深远的影响 对更年期妇女的衰老具有重要意义。该项目针对冠状动脉 过度反应是心脏病增加的一个方面，相对而言 被忽视了。女性患心脏病的风险随着年龄的增长而显着增加 更年期期间与雌激素水平下降密切相关（E）， 更深刻的是黄体酮（P），在持续存在的情况下 非卵巢 E 和睾酮 (T) 的产生。雄激素途径，特别是 双氢睾酮（DHT）似乎很重要。 E&P&T的不平衡， 假设这 3 种卵巢类固醇会导致保护状态的丧失。 之前，我们发现即使雌激素亚生理水平恢复， 黄体酮可恢复卵巢切除患者的正常冠状动脉反应性 灵长类动物。在该项目中，经过手术的绝经猴将接受 2 次治疗 服用 E 和/或 P 数周，控制 DHT 水平，或增加 2 周 或在受控 E 和 P 期间 DHT 减少，以进一步探测冠状动脉 这 3 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 (TxA2) 受体。 DHT，已知最有效的 TxA2 受体诱导剂形成 冠状动脉局部，当存在缺陷时，超过 E 从 1 得出的值 如果没有 P，则平衡有利于将 T 转换为 DHT，而不是 E。 P 还直接抑制 TxA2 受体表达。小于阈值 P 为 因此假设这是三重不利影响。 E、P 和 TxA2 的研究 免疫细胞化学检测冠状动脉壁受体分布，TxA2 Scatchard 分析的受体结合、E、P 和 DHT 的血液水平、冠状动脉 Ca2+ 和蛋白激酶 C 的直径、血压和细胞研究 将探讨冠状动脉的病理生理机制 多次操作 E、P 和 DHT 导致的高反应性。体内 导管插入术实验室研究将与总体和 冠状动脉的组织病理学检查以确定相关性 具有高反应性和 TxA2 受体表达。 E、P 和 DHT 测试 对血管舒张剂和血管收缩剂变化背后的细胞因子的影响 灵长类动物冠状动脉对于了解如何保护冠状动脉非常重要 预防绝经后衰老过程中的冠状动脉风险。