Estrogen modulation of fibroblast function in the pressure overloaded heart

雌激素对压力超负荷心脏成纤维细胞功能的调节

基本信息

批准号：
7799997
负责人：
WAYNE E CARVER
金额：
$ 3.56万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-16 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7799997
关键词：
17p Address Adhesions Affect Angiotensin II Angiotensins Animals Attenuated Behavior Biochemical Biological Assay Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell model Cells Collagen Data Estradiol Estrogen Receptors Estrogens Extracellular Matrix Female Fibroblast Growth Factor Fibroblasts Fibrosis Gender Gene Expression Growth Growth Factor Heart Heart Diseases Heart Hypertrophy Heart failure Hormonal Hormones Hypertrophy Mechanics Mediating Mediator of activation protein Modeling Molecular Myocardial Myocardial dysfunction Myocardium Ovarian hormone Physiology Play Premenopause Process Production Regulation Research Personnel Role Signal Pathway Signal Transduction Stretching Testing Thinking Tissues Ventricular Remodeling attenuation cell type constriction design in vitro Model in vivo interstitial male pressure programs research study response

项目摘要

DESCRIPTION (provided by applicant): Increased cardiovascular load results in an adaptive process including myocardial hypertrophy and fibrosis. In pathological situations, this adaptive response can progress into myocardial dysfunction and eventually heart failure. Premenopausal females are relatively protected from cardiovascular diseases including loadinduced hypertrophy and heart failure. Recent studies have illustrated that the ovarian hormone, 17 betaestradiol plays an essential role in mediating gender-specific cardioprotection; however, many questions remain regarding the molecular and cellular mechanisms of these effects. Interstitial fibroblasts are critical to myocardial function as these cells produce and remodel the myocardial extracellular matrix. Alterations in the organization and accumulation of the extracellular matrix can deleteriously affect myocardial function and are thought to be important determinants in the progression to heart failure. Little is known regarding the effects of gender and ovarian hormones in the regulation of fibroblast gene expression and function. The proposed studies will determine the effects of gender and 17 beta- estradiol on myocardial fibrosis. These studies will test the over-riding hypothesis that gender-specific differences in the progression of cardiac fibrosis are due to the direct attenuation of the fibroblast response to pro-fibrotic biochemical factors and mechanical forces by 17 beta-estradiol. Specific Aims designed to test this hypothesis include: 1) to determine the effects of gender and 17 beta- estradiol on fibroblast behavior and gene expression in the pressure overloaded myocardium, 2) to determine the mechanisms whereby 17 beta- estradiol represses the pro-fibrotic response of cardiac fibroblasts to angiotensin II and 3) to elucidate the mechanisms through which 17 beta- estradiol attenuates the response of cardiac fibroblasts to mechanical stretch. These studies will utilize whole animal and isolated cell models to assay the effects of gender and 17 beta- estradiol on fibroblast gene expression and behavior (contractility, proliferation and adhesion). The proposed studies will conclusively determine the effects of gender and ovarian hormones on myocardial fibrosis and will begin to elucidate the molecular mechanisms of these effects. These studies will be important towards understanding the cardioprotective mechanisms of gender in heart diseases involving the myocardial interstitium.

描述（由申请人提供）：心血管负荷增加导致适应性过程，包括心肌肥大和纤维化。在病理情况下，这种适应性反应可能进展为心肌功能障碍并最终导致心力衰竭。绝经前女性相对免受心血管疾病的影响，包括负荷引起的肥大和心力衰竭。最近的研究表明，卵巢激素 17 β-雌二醇在介导性别特异性心脏保护方面发挥着重要作用。然而，关于这些效应的分子和细胞机制仍然存在许多问题。间质成纤维细胞对心肌功能至关重要，因为这些细胞产生并重塑心肌细胞外基质。细胞外基质的组织和积累的改变会对心肌功能产生有害影响，并被认为是心力衰竭进展的重要决定因素。关于性别和卵巢激素在成纤维细胞基因表达和功能调节中的影响知之甚少。拟议的研究将确定性别和 17 β-雌二醇对心肌纤维化的影响。这些研究将检验最重要的假设，即心脏纤维化进展中的性别特异性差异是由于成纤维细胞对促纤维化生化因素和 17 β-雌二醇机械力的反应直接减弱所致。旨在检验这一假设的具体目标包括：1) 确定性别和 17 β-雌二醇对压力超负荷心肌中成纤维细胞行为和基因表达的影响，2) 确定 17 β-雌二醇抑制促纤维化的机制心脏成纤维细胞对血管紧张素 II 的反应和 3) 阐明 17 β-雌二醇减弱心脏成纤维细胞反应的机制成纤维细胞进行机械拉伸。这些研究将利用整个动物和分离的细胞模型来测定性别和 17 β-雌二醇对成纤维细胞基因表达和行为（收缩性、增殖和粘附）的影响。拟议的研究将最终确定性别和卵巢激素对心肌纤维化的影响，并将开始阐明这些影响的分子机制。这些研究对于了解涉及心肌间质的心脏病中性别的心脏保护机制具有重要意义。