HORMONE REGULATION OF CARDIAC INJURY
心脏损伤的激素调节
基本信息
- 批准号:7381200
- 负责人:
- 金额:$ 25.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-05-01 至 2007-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The central hypothesis of this proposal is that HDL-associated sex hormones (estrogen and testosterone) regulate the activity of cardiac myocyte constitutive nitric oxide synthase which subsequently affects the extent of ischemic injury. Epidemiological studies demonstrate that women are less prone to ischemic heart disease than men. The mechanisms responsible the differences in ischemic injury observed between men and women are not know although the current focus is on sex hormones, in particular estrogen and testosterone. A large number of studies have implicated estrogen-induced stimulation of constitutive nitric oxide synthase (cNOS) as providing protection against ischemic injury of cardiac myocytes. The role of testosterone is unclear with reports of protection against ischemic injury and reports of testosterone promoting ischemic injury. The majority of the studies on estrogen and testosterone do not distinguish between effects mediated by the endothelium in hearts and cardiac myocytes. One of the novel aspects of the proposed studies is that the preliminary data indicate that estrogen and testosterone have direct effects on cardiac myocytes, independent of the endothelium. Another novel aspect of the proposed studies is that it is estrogen or testosterone associated with HDL that is responsible for the generation of nitric oxide in cardiac myocytes and protection/promotion of ischemic injury. The molecular mechanism whereby estrogen limits ischemic injury and testosterone increases ischemic injury will be tested in two Aims. Aim 1: To determine the mechanism whereby HDL-associated estrogen stimulates the production of nitric oxide and limits ischemic injury. The preliminary studies suggest that estrogen receptor alpha and caveolin-1 form a complex that stimulates cNOS via AMP kinase. Cardiac myocytes isolated from wild type mice, caveolin-1 null mice, or estrogen receptor alpha null mice will be used along with dominant negative adenoviral constructs, agonist/antagonists, and enzyme assays to dissect the mechanism(s). In addition, wild type mice, SR-BI null mice, caveolin-1 null mice, and estrogen receptor alpha null mice along with ovariectomies and ovariectomies/estrogen replacement will be used to determine the effect on ischemic injury. Aim 2: To determine the mechanism whereby HDL-associated testosterone decreases the generation of nitric oxide and increases ischemic injury. The preliminary studies demonstrate that HDL-associated testosterone decreases the generation of nitric oxide without affecting the cellular levels of cNOS. Isolated cardiac myocytes will be used to examine several possible mechanisms for the HDL-testosterone mediated inhibition of cNOS such as, altered caveolin binding to cNOS, depletion of caveolae cholesterol, re-localization of cNOS, and modification of cNOS and/or caveolin-1. Additional studies will determine if the androgen receptor and/or testosterone uptake are involved in this process. Wild type mice, SR-BI null mice, and caveolin-1 null mice along with orchidectomies and orchidectomies/testosterone replacement will be used to determine the effect on ischemic injury.
该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者(PI)可能从另一个NIH来源获得主要资金,因此可以在其他CRISP条目中表示。所列机构为中心,不一定是研究者所在机构。该建议的中心假设是HDL相关性激素(雌激素和睾酮)调节心肌细胞组成型一氧化氮合酶的活性,其随后影响缺血性损伤的程度。 流行病学研究表明,女性比男性更不容易患缺血性心脏病。虽然目前的研究重点是性激素,特别是雌激素和睾酮,但造成男女之间缺血性损伤差异的机制尚不清楚。大量研究表明,雌激素诱导的组成型一氧化氮合酶(cNOS)刺激可以保护心肌细胞免受缺血性损伤。睾酮的作用尚不清楚,有报告称睾酮可保护缺血性损伤,也有报告称睾酮可促进缺血性损伤。大多数关于雌激素和睾酮的研究没有区分心脏内皮细胞和心肌细胞介导的效应。这项研究的一个新方面是,初步数据表明,雌激素和睾酮对心肌细胞有直接影响,而不依赖于内皮细胞。提出的研究的另一个新方面是,与HDL相关的雌激素或睾酮负责心肌细胞中一氧化氮的产生和缺血性损伤的保护/促进。雌激素限制缺血性损伤和睾酮增加缺血性损伤的分子机制将在两个目标中进行测试。 目的1:探讨高密度脂蛋白相关雌激素刺激一氧化氮产生和限制缺血性损伤的机制。初步研究表明,雌激素受体α和小窝蛋白-1形成复合物,通过AMP激酶刺激cNOS。从野生型小鼠、小窝蛋白-1缺失小鼠或雌激素受体α缺失小鼠分离的心肌细胞将与显性阴性腺病毒构建体、激动剂/拮抗剂和酶测定一起沿着使用,以剖析机制。此外,将使用野生型小鼠、SR-BI缺失小鼠、小窝蛋白-1缺失小鼠和雌激素受体α缺失小鼠以及卵巢切除术和卵巢切除术/雌激素替代沿着来确定对缺血性损伤的影响。 目的2:探讨高密度脂蛋白相关睾酮减少一氧化氮生成和增加缺血性损伤的机制。初步研究表明,HDL相关的睾酮减少一氧化氮的产生,而不影响cNOS的细胞水平。分离的心肌细胞将用于检查HDL-睾酮介导的cNOS抑制的几种可能机制,例如改变的小窝蛋白与cNOS的结合、小窝胆固醇的消耗、cNOS的重新定位以及cNOS和/或小窝蛋白-1的修饰。进一步的研究将确定雄激素受体和/或睾酮摄取是否参与这一过程。将使用野生型小鼠、SR-BI缺失小鼠和小窝蛋白-1缺失小鼠沿着进行睾丸切除术和睾丸切除术/睾酮替代来确定对缺血性损伤的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Eric J Smart其他文献
Eric J Smart的其他文献
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{{ truncateString('Eric J Smart', 18)}}的其他基金
Proteomic identification of diabetes biomarkers
糖尿病生物标志物的蛋白质组学鉴定
- 批准号:
7127983 - 财政年份:2006
- 资助金额:
$ 25.05万 - 项目类别:
Proteomic identification of diabetes biomarkers
糖尿病生物标志物的蛋白质组学鉴定
- 批准号:
7268126 - 财政年份:2006
- 资助金额:
$ 25.05万 - 项目类别:
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