Estrogen modulation of fibroblast function in the pressure overloaded heart

描述(申请人提供)：心血管负荷增加会导致一种适应性过程，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会发展为心肌功能障碍，最终导致心力衰竭。绝经前的女性相对免受心血管疾病的影响，包括负荷性肥厚和心力衰竭。最近的研究表明，卵巢激素17倍雌二醇在调节特定性别的心脏保护中起着重要作用；然而，关于这些作用的分子和细胞机制仍有许多问题。间质成纤维细胞对心肌功能至关重要，因为这些细胞产生和重塑心肌细胞外基质。细胞外基质的组织和积聚的改变可以有害地影响心肌功能，并被认为是进展为心力衰竭的重要决定因素。关于性别和卵巢激素在调节成纤维细胞基因表达和功能中的作用，我们知之甚少。这项拟议的研究将确定性别和17β-雌二醇对心肌纤维化的影响。这些研究将检验压倒一切的假设，即心脏纤维化进展中的性别差异是由于17β-雌二醇直接减弱了成纤维细胞对促纤维化生化因素和机械力的反应。为验证这一假说而设计的具体目标包括：1)确定性别和17β-雌二醇对压力超负荷心肌成纤维细胞行为和基因表达的影响；2)确定17β-雌二醇抑制心脏成纤维细胞对血管紧张素II的促纤维化反应的机制；3)阐明17β-雌二醇减弱心脏成纤维细胞对机械拉伸的反应的机制。这些研究将利用整个动物和分离的细胞模型来分析性别和17β-雌二醇对成纤维细胞基因表达和行为(收缩、增殖和粘连)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疾病中性别的心脏保护机制将是重要的。

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.