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: 9084473
• 负责人: LEANNE GROBAN
• 金额: $ 31.78万
• 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/9084473
• 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; Data; Detection; Development; Diastolic heart failure; Echocardiography; Elderly; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Extracellular Matrix; Female; Fibrosis; Fluorescence; Functional disorder; Future; G-Protein-Coupled Receptors; GPER gene; Gene Deletion; Gene Silencing; Genes; Goals; Health; Heart; Heart Diseases; Heart failure; High Prevalence; Hypertension; Hypertrophy; Intervention; Knockout Mice; Knowledge; Lead; Left; Left Ventricular Remodeling; Light; Link; Maintenance; Mechanics; Mediating; Menopause; Methodology; Modeling; Molecular; Mus; Muscle Cells; Myocardial; Myocardial dysfunction; NADPH Oxidase; Norway; Orphan; 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; coronary fibrosis; deprivation; hemodynamics; improved; inhibitor/antagonist; innovation; interstitial; knock-down; middle age; normal aging; older women; pressure; prevent; 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）：绝经后女性中左心室舒张功能障碍（LVDD）的患病率较高，表明与雌激素丢失有关。由于绝经后LVDD可能进展为舒张性心力衰竭，因此非常需要雌激素替代疗法的心血管益处而无其不良反应的疗法。我们的长期目标是更好地了解一种新的雌激素受体GPR 30在维持女性心脏结构和功能中的作用，以及雌激素丧失后和衰老期间心脏重塑和LVDD的潜在机制。本申请的目的是揭示GPR 30信号传导的心脏保护作用和与局部肾素-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女性LVDD的进展。具体来说，我们将确定GPR 30和糜酶介导的血管紧张素II（Ang II）的形成和适应不良的途径，导致纤维化和lustropic功能障碍，使用雌激素敏感的动物模型的心脏老化之间的细胞内关系。我们的中心假设是GPR 30激活通过抑制细胞内糜酶/Ang II有利地调节心脏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， 左心室顺应性和舒张功能。在强有力的初步数据的指导下，我们将通过追求三个具体目标来验证我们的假设：1）表征GPR 30对糜酶介导的Ang II表达的抑制作用及其在大鼠和小鼠衰老和雌激素丢失过程中导致LV重构和LVDD的不利作用; 2）确定糜酶/RAS失活在GPR 30减轻心脏纤维化中的分子机制和作用;（3）探讨GPR 30对左心室肌细胞肥大和抗肥大性重构的内在调节及其与细胞内糜酶/RAS的相互作用。为了实现这些目标，我们将使用一个全球性的系统生物学方法，整合（a）生理学，细胞和分子方法学;（B）正常女性心血管衰老和年龄相关的心脏GPR 30失活的啮齿动物模型;和（c）培养的心脏成纤维细胞和心肌细胞来自老化的心脏与或不与GPR 30基因或糜酶基因沉默。我们的创新方法将整合来自生物体水平（整个动物/整个心脏）和单细胞水平的信息，以生成有价值的翻译数据，更准确地描述GPR 30/糜酶/RAS通路在心脏生理学和LVDD中的功能。这项研究意义重大，因为我们假设的证实将促进对雌激素如何保护绝经前心脏免受心脏病影响的理解，并为未来的临床研究提供动力，这些研究重点关注GPR 30激活和/或糜酶抑制在老年女性LVDD预防和治疗及其进展为心力衰竭中的疗效。