Advanced glycation end products and cardiovascular disease

描述（由申请人提供）：心血管疾病是西方国家发病率和死亡率的主要原因。晚期糖基化终产物（AGEs）是一种与动脉粥样硬化和心血管疾病的发病机制有关的生物活性分子。系统性AGEs的主要来源是体内产生的内源性AGEs和食物中发现的外源性AGEs。西方饮食富含AGEs，这些AGEs是在高温下加工食物时形成的。AGEs通过交联血管壁中的胶原蛋白、增加低密度脂蛋白的氧化以及通过激活AGE受体（AGE）增加炎症而在动脉粥样硬化中发挥作用。循环同种型包括内源性分泌型β-内酰胺酶（esophagus），一种分泌到血液中且缺乏受体的跨膜和细胞质部分的β-内酰胺酶剪接变体，以及已从细胞表面裂解的β-内酰胺酶截短形式。基于对AGE-E2通路的了解和我们的初步数据，我们假设血清AGEs、sIgA和esIgA升高的老年人发生不良心血管结局（如冠心病、心力衰竭、中风和心血管疾病死亡率）的风险更大。我们建议在NIH支持的健康、衰老和身体组成（健康ABC）研究（一项基于社区的前瞻性老龄化研究）中描述AGEs和循环血管与心血管结局之间的关系。将在入组时测量血清AGEs和循环RAGE，并检查其与流行心血管疾病和已在十年随访中评估的突发心血管疾病的关系。还将检查血清AGEs和循环血管紧张素转换酶与主动脉脉搏波速度、异常葡萄糖代谢和炎症标志物的关系。这项研究将确定血清AGEs是否是心血管疾病的主要危险因素，并将深入了解血清AGEs及其循环受体可能参与心血管疾病发病机制的生物学机制。AGEs是一个潜在的可改变的风险因素，因为循环AGEs可以通过饮食调整和AGEs抑制剂或AGE-breakers的药物干预来降低。公共卫生相关性：该项目与公共卫生有关，因为它旨在描述晚期糖基化终产物，西方饮食中大量发现的生物活性化合物与老年人心血管疾病之间的关系。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in western countries. Advanced glycation end products (AGEs) are bioactive molecules implicated in the pathogenesis of atherosclerosis and cardiovascular disease. Major sources of systemic AGEs are endogenous AGEs generated in the body and exogenous AGEs found in foods. The western diet is rich in AGEs that are formed when food is processed at high temperatures. AGEs play a role in atherosclerosis by cross-linking collagen in vessel walls, increasing oxidation of low-density lipoprotein, and increasing inflammation through activation of the receptor for AGE (RAGE). Circulating isoforms of RAGE include endogenous secretory RAGE (esRAGE), a splice variant of RAGE that is secreted into blood and lacks the transmembrane and cytoplasmic portion of the receptor, and truncated forms of RAGE that have been cleaved from the cell surface. Based upon knowledge of the AGE-RAGE pathway and our preliminary data, we hypothesize that older people with elevated serum AGEs, sRAGE, and esRAGE are at greater risk of developing adverse cardiovascular outcomes, such as coronary heart disease, heart failure, stroke, and cardiovascular disease mortality. We propose to characterize the relationship between AGEs and circulating RAGE with cardiovascular outcomes in the NIH-supported Health, Aging and Body Composition (Health ABC) Study, a community-based prospective study of aging. Serum AGEs and circulating RAGE will be measured at enrollment and examined in relation to prevalent cardiovascular disease and to incident cardiovascular diseases that have been assessed over ten years of follow-up. Serum AGEs and circulating RAGE will also be examined in relation to aortic pulse wave velocity, abnormal glucose metabolism, and markers of inflammation. The proposed study will determine whether or not serum AGEs are a major risk factor for cardiovascular disease and will provide insight into the biological mechanisms by which serum AGEs and their circulating receptors may be involved in the pathogenesis of cardiovascular disease. AGEs are a potentially modifiable risk factor, as circulating AGEs can be lowered by dietary modification and by pharmacological intervention with AGE inhibitors or AGE-breakers. PUBLIC HEALTH RELEVANCE: This project is relevant to public health as it aims to characterize the relationship between advanced glycation end products, bioactive compounds found in high amounts in the western diet, and cardiovascular disease in older adults.