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，这导致了强烈的搜索对于CVD风险因素。最近的努力集中在新型CVD风险因素上，因为常规风险因素可能解释<CVD的50％。内皮祖细胞（EPC）是这样一种新型的CVD风险因素。耐力运动训练增加了EPC的数量；但是，大多数以前的研究仅评估了EPC数量和菌落形成单元，代表EPC功能的最小表征。该提议扩大了我们以前研究了离体训练相关变化的细胞/分子机制 EPC功能，使用横截面比较与久坐的老年人的运动训练结合以及受耐力训练的运动员的训练停止。我们还将确定这些培训是否 - 诱导的变化转化为改善体内内皮功能。更好地表征ex Vivo EPC函数我们将测量NADPH氧化酶活性和表达，一氧化氮（NO）和活性氧（ROS）在标准和动脉粥样硬化培养物下，CD34+衍生的假定EPC中的水平和管形成环境。我们的假设1是，在横截面的基础上，年长的运动员将拥有更好的EPC 在标准培养条件下的功能和对动脉粥样硬化培养环境的响应匹配久违的人。我们对“更好” EPC功能的定义是较低的EPC NADPH 氧化酶表达/活性和ROS水平以及较高的NO水平和管形成。我们还将评估体内内皮功能以确定是否可以用作离体EPC功能的临床指数。我们的假设2是，久坐的人的运动训练将有所改善，并在年龄较大运动员会恶化，在标准培养条件下的体内EPC功能以及对动脉粥样硬化的响应环境和体内内皮功能。这些结果将使我们能够有效地得出锻炼训练可改善体内EPC和体内内皮功能。然后，我们将通过操纵NADPH氧化酶活性，培养物中无水平来评估EPC在哪种程度通过模仿运动员明显的细胞内EPC环境，可以改善久坐的受试者。我们的假设3是抑制NADPH氧化酶的均和来自假定的EPC的细胞内NO的增加停止训练后，久坐的人和运动员的体内EPC功能将提高到水平类似于受过训练的运动员。这种机械方法将使我们能够量化运动训练对EPC功能的影响是EPC NADPH氧化酶活性变化的功能。很少研究已经解决了EPC，作为一种新型CVD风险因素和运动训练以及几乎没有研究使用人类受试者，并将研究扩展到细胞，代谢和机械水平。因此，我们处于独特的位置，可以显着扩展我们对基于这种新型CVD风险因素的运动训练的好处的机制。