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

描述（由申请人提供）：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，无特异性治疗。绝经前妇女似乎免受舒张功能障碍，其发病率在绝经后迅速增加。临床证据有力地表明，雌激素丧失和心脏肾素-血管紧张素-醛固酮系统（RAAS）激活之间的相互作用有助于绝经后妇女高血压和左心室肥厚的发展，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（一种新型遗传品系）的早期雌激素耗竭会触发舒张功能障碍的发展，表现为伪异常多普勒模式和E/ E′增加（反映高充盈压力）；这与心脏胶原蛋白和血清醛固酮增加有关。这些数据导致了总体假设，即雌激素的缺失调节了心脏RAAS内的两个关键酶途径，以增强和抑制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-的减少（1-7），促进左室重构和舒张僵硬。通过对卵巢切除与雌激素完整的mRen2大鼠进行反向翻译，我们将确定：1)心脏RAAS从抗纤维化肢体到促纤维化肢体的转变是否有助于雌激素缺失后的左室重塑和舒张功能障碍；2)雌激素替代通过改变RAAS与ACE2和血管紧张素-的平衡来减轻舒张功能障碍（1-7）；3) ACE2抑制减弱了雌激素的心脏保护作用。这项研究的结果很重要，因为舒张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法尚未明确。公共卫生相关性：舒张功能障碍对老年妇女的主要问题——年龄相关性心力衰竭有显著影响。本建议的总体目标是通过建立高血压和手术绝经的啮齿动物模型，描述雌激素在心脏肾素-血管紧张素-醛固酮系统调节中导致心脏重塑和舒张功能障碍的作用。我们的结果将有助于阐明绝经后妇女舒张期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.