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

描述(申请人提供)：老年女性心力衰竭与老年男性不同，由于心脏僵硬增加，舒张性功能障碍更常见，对此没有特定的治疗方法。绝经前的女性似乎不受舒张期功能障碍的影响，绝经后其发病率迅速增加。临床证据有力地表明，雌激素丢失和心脏肾素-血管紧张素-醛固酮系统(RAAS)激活之间的相互作用导致绝经后妇女高血压和左室肥厚的发生，而高血压和左心室肥厚是舒张期功能障碍的两个危险因素。我们发现，雌性mRen2 Lewis大鼠早期雌激素缺乏会触发舒张期功能障碍的发展，表现为假性正常的多普勒模式和E/e‘(反映高充盈压)的增加；这与心肌胶原蛋白和血清醛固酮的增加有关。这些数据导致了一个总体假设，即雌激素的丢失调节心脏RAAS内的两个关键酶途径，以增强ACE和抑制ACE2。这两种酶的失衡最终导致血管紧张素II和醛固酮的持续表达，以及相应的血管紧张素-(1-7)的减少，促进左室重构和舒张期僵硬。在去卵巢的mRen2大鼠和雌激素保持不变的mRen2大鼠中，我们将使用反向翻译的方法，确定：1)心脏RAAS从抗纤维化的肢体转移到促纤维化的肢体是否有助于雌激素丢失后的左室重构和舒张期功能障碍；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)来缓解舒张性功能障碍；以及3)ACE2的抑制减弱了雌激素的心脏保护作用。这项研究的结果将是重要的，因为舒张期功能障碍在绝经后妇女中非常普遍，但其机制和最佳治疗方案尚未很好地确定。公共卫生相关性：舒张期功能障碍对老年女性的主要问题--年龄相关性心力衰竭有很大影响。这项建议的总体目标是利用已建立的高血压和外科绝经的啮齿动物模型来描述雌激素在心脏肾素-血管紧张素-醛固酮系统调节中的作用，因为雌激素导致心脏重构和舒张期功能障碍。我们的结果将有助于阐明绝经后妇女舒张性心脏病的最佳治疗方案。

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.