Sexual hormones, cardiac mast cells and cardioprotection

性激素、心脏肥大细胞和心脏保护

• 批准号: 7116356
• 负责人: Joseph S Janicki
• 金额: $ 35.4万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116356
• 关键词: SDS polyacrylamide gel electrophoresis; cardiogenesis; collagen; congestive heart failure; cytoprotection; echocardiography; enzyme linked immunosorbent assay; estrogens; extracellular matrix; gender difference; heart function; hormone regulation /control mechanism; intracardiac volume; laboratory mouse; laboratory rat; mast cell; myocardium; protein degradation; radioimmunoassay; sex hormones; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): While cardiovascular disease is the leading cause of death in both men and women in the United States, it is only after menopause that the risk of developing congestive heart failure dramatically increases in women. The proposed study will investigate gender-specific differences in myocardial remodeling and the development of heart failure secondary to chronic volume overload. Specifically, the focus of this proposal will be estrogen's modulation of TNF-alpha production and release from cardiac mast cells. The overall hypothesis to be examined is that estrogen modulation of TNF-alpha is responsible for the gender differences in cardiovascular remodeling induced by chronic volume overload. To this end, the following specific aims will be addressed using a variety of physiological, biochemical, morphological and molecular techniques to delineate the mechanisms responsible for the gender-specific differences in cardiovascular function and the temporal progression of adverse ventricular remodeling induced secondary to either infrarenal aortocaval fistula or TNF-alpha infusion in rats. Aim 1: Does estrogen alter the dynamic remodeling process induced by chronic volume overload? Aim 2: What role does the estrogen modulation of TNF-alpha play in myocardial remodeling and development of heart failure? Aim 3: Is estrogen modulation of mast cell-derived TNF-alpha the mechanism responsible for cardioprotection observed in intact females? In summary, the proposed studies will provide a well integrated approach designed to fill a void in our understanding of the mechanisms responsible for the cardioprotection observed in premenopausal females. We have every expectation that the investigations will significantly increase our understanding of the important interactions between estrogen, cardiac mast cell-derived TNF-alpha, cardiac fibroblasts, myocytes, and the extracellular matrix during cardiovascular remodeling secondary to chronic volume overload and advance the development of novel therapeutic approaches for the prevention of heart failure.

描述（由申请人提供）：虽然心血管疾病是美国男性和女性死亡的主要原因，但只有在绝经后，女性发生充血性心力衰竭的风险才会急剧增加。这项拟议的研究将调查心肌重构和慢性容量过载继发心力衰竭的性别差异。具体来说，本提案的重点将是雌激素对心脏肥大细胞中tnf - α产生和释放的调节。要检验的总体假设是，雌激素对tnf - α的调节是慢性容量过载引起的心血管重构的性别差异的原因。为此，以下具体目标将利用各种生理、生化、形态学和分子技术来描述大鼠肾下主动脉腔瘘或tnf - α输注引起的心血管功能的性别差异和不良心室重构的时间进展的机制。目的1：雌激素是否改变慢性容量过载诱导的动态重塑过程？目的2：雌激素对tnf - α的调节在心肌重塑和心力衰竭的发展中起什么作用？目的3：雌激素对肥大细胞来源的tnf - α的调节是在完整女性中观察到的心脏保护机制吗？总之，拟议的研究将提供一个很好的综合方法，旨在填补我们对绝经前女性观察到的心脏保护机制的理解空白。我们期望这项研究将显著增加我们对雌激素、心肌肥大细胞衍生的tnf - α、心脏成纤维细胞、肌细胞和细胞外基质在慢性容量过载引起的心血管重塑过程中的重要相互作用的理解，并促进预防心力衰竭的新治疗方法的发展。