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

描述（由申请人提供）：老年女性心力衰竭与老年男性不同，由于心脏僵硬度增加，舒张功能障碍更频繁，对此没有特异性治疗。绝经前妇女似乎不受舒张功能障碍的影响，绝经后其发病率迅速增加。临床证据有力地表明，雌激素损失和心脏肾素-血管紧张素-醛固酮系统（RAAS）的激活之间的相互作用有助于绝经后妇女高血压和左心室（LV）肥大的发展，舒张功能障碍的两个危险因素。我们已经发现，雌性mRen 2刘易斯大鼠（一种新的同类品系）的早期雌激素耗竭引发舒张功能障碍的发展，表现为异常多普勒模式和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。这些数据导致的总体假设，雌激素的损失调节两个关键的酶途径内的心脏RAAS，以提高ACE和抑制ACE 2。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，以及血管紧张素-（1-7）的相应减少，促进LV重塑和舒张僵硬。在卵巢切除与雌激素完整的mRen 2大鼠中使用反向翻译方法，我们将确定：1）心脏RAAS从抗纤维化分支向促纤维化分支的转变是否有助于雌激素丢失后的LV重构和舒张功能障碍; 2）雌激素替代通过将RAAS的平衡转变为ACE 2和血管紧张素-（1-7）来减轻舒张功能障碍;和3）ACE 2抑制减弱雌激素的心脏保护益处。这项研究的结果将是重要的，因为舒张功能障碍是非常普遍的绝经后妇女，但机制，因此最佳的治疗还没有得到很好的界定。公共卫生相关性：舒张功能障碍是老年女性的主要问题，与年龄相关的心力衰竭的重要原因。该建议的总体目标是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，使用已建立的高血压和手术绝经的啮齿动物模型。我们的研究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法。

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.