Estrogen, Angiotensin-(1-7), and Diastolic Function

雌激素、血管紧张素-(1-7) 和舒张功能

• 批准号: 8288151
• 负责人: LEANNE GROBAN
• 金额: $ 28.87万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288151
• 关键词: Address; Aging; Agonist; Aldosterone; Angiotensin II; Attenuated; Cardiac; Clinical; Collagen; Congenic Strain; Coupled; Data; Development; Elderly woman; Enzymes; Equilibrium; Estrogen Receptors; Estrogen Replacements; Estrogens; Exhibits; Female; Functional disorder; GTP-Binding Proteins; Goals; Health; Heart; Heart Diseases; Heart failure; Hypertension; Impairment; Incidence; Lead; Left; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Left ventricular structure; Limb structure; MLN4760; Menopause; Modeling; Morbidity - disease rate; Nitric Oxide; Nitric Oxide Synthase; Operative Surgical Procedures; Ovarian hormone; Ovariectomy; Pathway interactions; Pattern; Phenotype; Population; Positioning Attribute; Postmenopause; Premenopause; Rattus; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Regulatory Pathway; Renin-Angiotensin System; Renin-Angiotensin-Aldosterone System; Research Personnel; Risk Factors; Rodent Model; Role; Serum; Structure; System; Ventricular; Woman; Work; age related; angiotensin I (1-7); congenic; experience; inhibitor/antagonist; men; mortality; novel; pressure; prevent; receptor; sex; translational approach

DESCRIPTION (provided by applicant): Heart failure in aging women differs from that in aging men, with more frequent diastolic dysfunction due to increased cardiac stiffness, for which there is no specific treatment. Premenopausal women appear to be protected from diastolic dysfunction, with a rapid increase in its incidence after menopause. Clinical evidence strongly suggests that the interaction between estrogen loss and activation of the cardiac renin-angiotensin-aldosterone system (RAAS) contributes to the development of hypertension and left ventricular (LV) hypertrophy in postmenopausal women, two risk factors for diastolic dysfunction. We have found that early estrogen depletion in the female mRen2 Lewis rat, a novel congenic strain, triggers the development of diastolic dysfunction, manifested by a pseudonormal Doppler pattern and increase in E/e' (reflective of high filling pressures); this is associated with increased cardiac collagen and serum aldosterone. These data lead to the overall hypothesis that loss of estrogen regulates two key enzymatic pathways within the cardiac RAAS to enhance ACE and suppress ACE2. The imbalance in these two enzymes ultimately results in sustained expression of angiotensin II and aldosterone, and a corresponding reduction in angiotensin-(1-7), promoting LV remodeling and diastolic stiffness. Using a reverse translational approach in ovariectomized versus estrogen-intact mRen2 rats, we will determine whether: 1) a shift from the antifibrotic to profibrotic limb of the cardiac RAAS contributes to LV remodeling and diastolic dysfunction following estrogen loss; 2) estrogen replacement attenuates diastolic dysfunction by shifting the balance of the RAAS to ACE2 and angiotensin-(1-7); and 3) ACE2 inhibition attenuates the cardioprotective benefits of estrogen. The results from this study will be important because diastolic dysfunction is highly prevalent among postmenopausal women, yet the mechanisms and therefore optimal therapy are not well defined. PUBLIC HEALTH RELEVANCE: Diastolic dysfunction contributes significantly to age-related heart failure, a major problem among elderly women. The overall goal of this proposal is to delineate the role of estrogen in the modulation of the cardiac renin-angiotensin-aldosterone system as it leads to cardiac remodeling and diastolic dysfunction using an established rodent model of hypertension and surgical menopause. Our results will help clarify optimal treatment of diastolic heart disease in postmenopausal women.

描述（申请人提供）：老年女性的心力衰竭与老年男性的心力衰竭不同，由于心脏僵硬度增加，舒张功能障碍更常见，对此没有具体的治疗方法。绝经前女性似乎不会出现舒张功能障碍，但绝经后其发病率迅速增加。临床证据强烈表明，雌激素减少与心脏肾素-血管紧张素-醛固酮系统（RAAS）激活之间的相互作用会导致绝经后女性高血压和左心室（LV）肥大，这是舒张功能障碍的两个危险因素。我们发现，雌性 mRen2 Lewis 大鼠（一种新型同源品系）的早期雌激素耗尽会引发舒张功能障碍，表现为伪正常多普勒模式和 E/e' 增加（反映高充盈压）；这与心脏胶原蛋白和血清醛固酮增加有关。这些数据得出总体假设：雌激素的丧失调节心脏 RAAS 内的两个关键酶途径，以增强 ACE 并抑制 ACE2。这两种酶的不平衡最终导致血管紧张素 II 和醛固酮的持续表达，以及血管紧张素-(1-7) 的相应减少，促进左心室重塑和舒张期僵硬度。在卵巢切除大鼠与雌激素完整 mRen2 大鼠中使用反向翻译方法，我们将确定：1）心脏 RAAS 从抗纤维化肢体向促纤维化肢体的转变是否会导致雌激素丧失后的左室重塑和舒张功能障碍； 2) 雌激素替代通过将 RAAS 的平衡转移到 ACE2 和血管紧张素-(1-7) 来减轻舒张功能障碍； 3) ACE2 抑制会减弱雌激素的心脏保护作用。这项研究的结果非常重要，因为舒张功能障碍在绝经后女性中非常普遍，但其机制和最佳治疗方法尚未明确。公共卫生相关性：舒张功能障碍会导致与年龄相关的心力衰竭，这是老年女性的一个主要问题。该提案的总体目标是利用已建立的高血压和手术绝经的啮齿动物模型来描述雌激素在调节心脏肾素-血管紧张素-醛固酮系统中的作用，因为它会导致心脏重塑和舒张功能障碍。我们的结果将有助于阐明绝经后女性舒张性心脏病的最佳治疗方法。