Endothelial Dysfunction, Oxidative Stress and Risk of Peripheral Arterial Disease

外周动脉疾病（peripheral arterial disease，PAD）是全身动脉粥样硬化的一种常见病，但其流行病学和危险因素的研究相对较少。内皮功能障碍及其与氧化应激、炎症和肾功能不全的关系可能是PAD发展和预后的重要途径。在PAD患者中经常观察到内皮功能障碍，新的研究表明它可以前瞻性地预测PAD，但缺乏关于内皮功能、氧化应激、炎症和肾功能在PAD发展中作用的大型前瞻性研究。我们提出了一种多方面的方法来评估内皮功能，氧化应激及其相关因素在PAD发展中的作用，使用两个定义明确的，大型的，仔细跟踪的美国男性和女性队列-护士健康研究和健康专业人员随访研究。这两项研究都包括20多年的重复饮食和生活方式问卷调查数据，从NHS的32，826名女性和HPFS的18，225名男性的子样本中收集的血液样本，以及前瞻性报告的临床重要PAD病例。目前的提案将利用这些丰富的资源来检查与内皮功能和氧化应激相关的几个标志物，它们彼此之间的相互关系和其他心血管危险因素，以及它们与PAD发展的关系。内皮功能障碍通过细胞间粘附分子-1来测量。氧化应激的标志物包括存在于apoB颗粒和γ-谷氨酰转移酶上的氧化磷脂。与肾功能不全相关的血清标志物包括胱抑素-C和β-2微球蛋白。最后，我们将研究如何派生的饮食抗氧化剂评分，根据测量的氧化电位的特定食物使用铁还原/抗氧化能力的方法，与PAD。

Peripheral arterial disease (PAD) is a highly prevalent, frequently morbid manifestation of systemic atherosclerosis, but relatively little attention has been paid to the epidemiology and risk factors for PAD. Endothelial dysfunction and its relationship with oxidative stress, inflammation, and renal insufficiency may be a critically important pathway in the development and prognosis of PAD. Endothelial dysfunction has been frequently observed among patients with PAD, and emerging studies suggest it may prospectively predict PAD, but large prospective studies of the roles of endothelial function, oxidative stress, inflammation, and renal function in the development of PAD are lacking. We propose a multi-faceted approach to evaluate the roles of endothelial function, oxidative stress, and their correlates in the development of PAD, using two well-defined, large, and carefully followed cohorts of U.S. men and women – the Nurses’ Health Study and the Health Professionals Follow-up Study. Both studies include over 20 years of repeated dietary and lifestyle questionnaire data, blood samples collected from subsamples of 32,826 women in NHS and 18,225 men in HPFS, and prospectively reported cases of clinically important PAD. The current proposal will use these rich resources to examine several markers related to endothelial function and oxidative stress, their interrelationships with each other and other cardiovascular risk factors, and their associations with development of PAD. Endothelial dysfunction is measured by intercellular adhesion molecule-1. Markers of oxidative stress include oxidized phospholipids present on apoB particles and γ-glutamyl transferase. Serum markers related to renal dysfunction include cystatin-C and β-2 microglobulin. Finally, we will examine how a derived dietary antioxidant score, based upon measured oxidative potential of specific foods using the ferric-reducing/antioxidant power method, is related to PAD.