Interplay Between Estrogen, GPR30 and Chymase/RAS in Diastolic Function

雌激素、GPR30 和食糜酶/RAS 在舒张功能中的相互作用

• 批准号: 8741901
• 负责人: LEANNE GROBAN
• 金额: $ 31.57万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8741901
• 关键词: Adult; Adverse effects; Affect; Age; Aging; Agonist; Angiotensin II; Animal Model; Animals; Area; Binding; Biochemistry; Calcium; Calcium Signaling; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Proliferation; Cell surface; Cells; Cellular Structures; Chronic; Chymase; Clinical Research; Collagen; Coupled; Data; Detection; Development; Diastolic heart failure; Echocardiography; Elderly; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Extracellular Matrix; Female; Fibrosis; Fluorescence; Functional disorder; Future; Gene Deletion; Gene Silencing; Genes; Goals; Heart; Heart Diseases; Heart failure; High Prevalence; Hypertension; Hypertrophy; Intervention; Knowledge; Lead; Left; Left Ventricular Remodeling; Light; Link; Maintenance; Mechanics; Mediating; Menopause; Methodology; Modeling; Molecular; Mus; Muscle Cells; Myocardial; NADPH Oxidase; Norway; Pathway interactions; Physiological; Physiology; Postmenopause; Premenopause; Prevention; Production; Quality of life; RBM5 gene; Rattus; Regulation; Relaxation; Renin-Angiotensin System; Replacement Therapy; Research; Risk; Rodent Model; Role; Signal Transduction; Small Interfering RNA; Source; Stimulus; Structure; Systems Biology; Testing; Tissues; Transfection; Uncertainty; Ventricular; Ventricular Function; Woman; Women' s Health; age related; aged; attenuation; cell growth; deprivation; estrophilin; hemodynamics; human GPRC5C protein; improved; inhibitor/antagonist; innovation; interstitial; mast cell; middle age; normal aging; older women; pressure; prevent; public health relevance; sex; therapeutic target

DESCRIPTION (provided by applicant): The higher prevalence of left ventricular diastolic dysfunction (LVDD) in postmenopausal women suggests a link with estrogen loss. Because LVDD may progress to diastolic heart failure after menopause, there is a significant need for therapies that confer the cardiovascular benefits of estrogen replacement therapy without its adverse effects. Our long-term goal is to better understand the role of a new estrogen receptor, GPR30, in the maintenance of cardiac structure and function in the female heart, and the mechanisms underlying cardiac remodeling and LVDD after estrogen loss and during aging. The objective of this application is to reveal the cardioprotective role of GPR30 signaling and interactions with the local renin-angiotensin system (RAS) and how this interaction affects the progression of LVDD in post-menopausal women. Specifically, we will determine the intracellular relationships between GPR30 and chymase-mediated angiotensin II (Ang II) formation and the maladaptive pathways that lead to fibrosis and lusitropic dysfunction, using estrogen-sensitive animal models of cardiac aging. Our central hypothesis is that GPR30 activation favorably regulates the structure and function of cardiofibroblasts and cardiomyocytes by inhibiting intracellular chymase/Ang II, thereby preserving the myocardial extracellular matrix, LV compliance, and diastolic function. Guided by strong preliminary data, we will test our hypothesis by pursuing three specific aims: 1) Characterize the inhibitory role of GPR30 on chymase-mediated Ang II expression and its adverse actions that lead to LV remodeling and LVDD during aging and estrogen loss in rats and mice; 2) Define the molecular mechanisms and roles of chymase/RAS deactivation in the attenuation of cardiac fibrosis by GPR30; and 3) Determine the intrinsic regulation of LV myocyte lusitropy and anti-hypertrophic remodeling by GPR30 and its interplay with intracellular chymase/RAS. To achieve these aims, we will use a global systems biology approach that integrates (a) physiological, cellular, and molecular methodologies; (b) rodent models of normal female cardiovascular aging and age-related cardiac GPR30 deactivation; and (c) cultured cardiofibroblasts and cardiomyocytes derived from the aging heart with or without GPR30 gene or chymase gene silencing. Our innovative approach will integrate information from both the organismal level (whole animal/whole heart) and the single-cell level to generate valuable translational data that more accurately describes GPR30/chymase/RAS pathway function in cardiac physiology and LVDD. The proposed research is significant because confirmation of our hypothesis will advance understanding of how estrogen protects the premenopausal heart from cardiac disease, and provide the impetus for future clinical studies focused on the efficacy of GPR30 activation and/or chymase inhibition in the prevention and treatment of LVDD, and its progression to heart failure, in aging women.

描述（由申请人提供）：绝经后妇女左室舒张功能障碍（LVDD）患病率较高，提示与雌激素减少有关。由于LVDD可能在绝经后发展为舒张性心力衰竭，因此需要一种具有雌激素替代疗法的心血管益处而无副作用的治疗方法。我们的长期目标是更好地了解一种新的雌激素受体GPR30在维持女性心脏结构和功能中的作用，以及雌激素缺失和衰老过程中心脏重塑和LVDD的机制。本应用的目的是揭示GPR30信号的心脏保护作用及其与局部肾素-血管紧张素系统（RAS）的相互作用，以及这种相互作用如何影响绝经后妇女LVDD的进展。具体来说，我们将利用雌激素敏感的心脏衰老动物模型，确定GPR30与乳糜酶介导的血管紧张素II （Ang II）形成之间的细胞内关系，以及导致纤维化和萎黄性功能障碍的不适应途径。我们的中心假设是GPR30的激活通过抑制细胞内酶/Ang II来有利地调节心肌成纤维细胞和心肌细胞的结构和功能，从而保护心肌细胞外基质。