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Potential Role of Endothelial Progenitor Cells in Cardiovascular Risk

内皮祖细胞在心血管风险中的潜在作用

基本信息

批准号：
8209089
负责人：
JAMES M HAGBERG
金额：
$ 17.46万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2013-11-30
项目状态：
已结题

项目摘要

Project Summary Cardiovascular disease (CVD) is the major cause of death in the US, which has resulted in an intense search for CVD risk factors. Recent efforts have focused on novel CVD risk factors, as conventional risk factors may explain <50% of CVD. Endothelial progenitor cells (EPCs) are one such novel CVD risk factor. Endurance exercise training increases EPC number; however, most previous studies assessed only EPC numbers and colony forming units, which represent a minimal characterization of EPC function. This proposal expands on our previous work to study the cellular/molecular mechanisms underlying training-related changes in ex vivo EPC function, using a cross-sectional comparison combined with exercise training in sedentary older adults and training cessation in older endurance-trained athletes. We also will determine whether these training- induced changes translate to improved in vivo endothelial function. To better characterize ex vivo EPC function we will measure NADPH oxidase activity and expression, nitric oxide (NO) and reactive oxygen species (ROS) levels, and tube formation in CD34+-derived putative EPCs, under both standard and atherogenic culture environments. Our Hypothesis #1 is, that on a cross-sectional basis, older athletes will have better ex vivo EPC function under standard culture conditions and in response to an atherogenic culture environment than matched older sedentary individuals. Our definition of "better" EPC function is lower ex vivo EPC NADPH oxidase expression/activity and ROS levels and higher NO levels and tube formation. We will also assess in vivo endothelial function to determine if it can be used as a clinical index of ex vivo EPC function. Our Hypothesis #2 is that exercise training in sedentary individuals will improve, and training cessation in older athletes will worsen, ex vivo EPC function under standard culture conditions and in response to an atherogenic environment and in vivo endothelial function. These results will allow us to validly conclude that exercise training improves ex vivo EPC and in vivo endothelial function. We will then perform mechanistic studies by manipulating NADPH oxidase activity and NO levels in cultures to assess the degree to which EPC function in sedentary subjects can be improved by mimicking the intracellular EPC milieu evident in athletes. Our Hypothesis #3 is that both inhibiting NADPH oxidase and increasing intracellular NO in putative EPCs from sedentary individuals and from athletes after stopping training will improve ex vivo EPC function to levels similar to those of trained athletes. This mechanistic approach will allow us to quantify the extent to which exercise training effects on EPC function are a function of changes in EPC NADPH oxidase activity. Very few studies have addressed the interaction between EPCs, as a novel CVD risk factor, and exercise training, and virtually no studies have utilized human subjects and extended the studies to the cellular, metabolic, and mechanistic levels. Thus, we are in a unique position to expand dramatically our understanding of the mechanisms that underlie the benefits of exercise training on this novel CVD risk factor.

项目摘要心血管疾病(CVD)是美国的主要死亡原因，人们对此进行了密集的搜索对于心血管疾病的危险因素。最近的努力集中在新的心血管疾病风险因素上，就像传统的风险因素可能解释50%的心血管疾病。内皮祖细胞是一种新的心血管危险因素。耐力运动训练增加了EPC数量；然而，以前的大多数研究只评估了EPC数量和菌落形成单位，代表EPC功能的最小特征。这项提案对以下内容进行了扩展我们之前的工作是在体外研究训练相关变化的细胞/分子机制久坐不动的老年人的EPC功能，采用横断面比较结合运动训练以及在接受耐力训练的老年运动员中停止训练。我们还将确定这些培训是否- 诱导的变化转化为体内内皮功能的改善。为了更好地表征体外EPC功能我们将检测NADPH氧化酶的活性和表达，一氧化氮(NO)和活性氧(ROS) CD34+来源的可能内皮祖细胞在标准培养和致动脉粥样硬化培养下的水平和管状形成环境。我们的假设1是，在横截面的基础上，年龄较大的运动员会有更好的体外EPC 在标准培养条件下的功能和对致动脉粥样硬化的培养环境的响应与久坐不动的老年人相匹配。我们对更好的EPC功能的定义是较低的体外EPC NADPH 氧化酶表达/活性和ROS水平，以及较高的NO水平和管状形成。我们还将在以确定体内内皮功能是否可作为体外EPC功能的临床指标。我们的假设2是久坐不动的人的运动训练会有所改善，而老年人停止训练运动员在标准培养条件下和对致动脉粥样硬化的反应时，体外EPC功能会恶化环境和体内内皮功能。这些结果将使我们能够有效地总结这一练习训练可改善体外内皮祖细胞和体内内皮功能。然后，我们将通过以下方式进行机械研究控制培养物中NADPH氧化酶活性和NO水平以评估EPC在久坐的受试者可以通过模仿运动员身上明显的细胞内EPC环境来改善。我们的假设3是抑制NADPH氧化酶和增加细胞内NO的可能的EPC从久坐的个体和运动员停止训练后将体外EPC功能提高到一定水平与训练有素的运动员相似。这种机械化的方法将使我们能够量化运动训练对EPC功能的影响是EPC NADPH氧化酶活性变化的函数。很少研究已经解决了作为一种新的心血管危险因素的内皮祖细胞与运动训练之间的相互作用，以及几乎没有一项研究利用人类受试者并将研究扩展到细胞、代谢和机械化的水平。因此，我们处于独特的地位，可以戏剧性地扩大我们对运动训练对这一新的心血管疾病危险因素的益处的机制。