Fetal Programming of Coronary Artery Disease

冠状动脉疾病的胎儿编程

• 批准号: 6745086
• 负责人: JEFFREY L SEGAR
• 金额: $ 14.01万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-02 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6745086
• 关键词: angiotensin II; angiotensin receptor; atherosclerosis; biological signal transduction; cardiovascular disorder risk; coronary artery; coronary disorder; dexamethasone; embryo /fetus; embryo /fetus monitoring; gene expression; glucocorticoids; immunocytochemistry; myocardium; northern blottings; oxidative stress; polymerase chain reaction; prenatal diagnosis; renin angiotensin system; sheep; superoxides; western blottings

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in the United States and other developed countries. In the United States alone, approximately 1 million individuals die from cardiovascular disease each year, nearly 50% of deaths from all causes. In addition to known associated risk factors for cardiovascular disease studies from the last decade suggest that influences during fetal life may predispose to coronary heart disease. There exist a number of potential mechanisms linking fetal adaptations to maternal and environmental influences to cardiovascular disease, including alterations in metabolic and endocrine functions, organ and tissue structure and gene expression. The renin-angiotensin system has been closely linked the development of endothelial dysfunction and progression to atherosclerosis. Previous studies of fetal programming demonstrate upregulation of key genes of the renin-angiotensin system and enhanced action of angiotensin II. We hypothesize that upregulation of the renin-angiotensin system in the coronary vasculature is an important aspect of fetal programming, resulting in increased oxidative stress and ultimately coronary endothelial dysfunction and coronary artery disease. We plan to use a developed model of fetal programming namely early prenatal exposure to dexamethasone in fetal sheep to further explore this hypothesis. Increased fetal exposure to glucocorticoids resulting from environmental influences on placental function appears to be an important mechanism of fetal programming. The specific aims of this proposal are to demonstrate that following prenatal exposure to dexamethasone, 1) coronary artery angiotensin II receptor gene expression is upregulated, 2) coronary vascular reactivity is altered, particularly in response to angiotensin, 3) vascular oxidative stress is enhanced, and 4) vascular gene expression profiles differ. We propose these differences are present early in life and persist throughout development. Studies of the effects of early dexamethasone exposure on coronary vascular function and vascular gene expression may provide an important link between adverse intrauterine environment and the subsequent development of atherosclerosis. Understanding these links and the specific mechanisms by which the altered fetal environment leads to disease in adulthood has important, worldwide public health implications. Only when the causes and mechanisms of hypertension and cardiovascular disease are understood in the context of a developmental process will it be possible to develop strategies for primary prevention.

描述（由申请人提供）：心血管疾病是美国和其他发达国家的首要死因。仅在美国，每年就有大约 100 万人死于心血管疾病，占所有原因死亡的近 50%。除了已知的心血管疾病相关危险因素之外，过去十年的研究表明，胎儿时期的影响可能会诱发冠心病。存在许多潜在机制将胎儿的适应与母体的适应以及环境对心血管疾病的影响联系起来，包括代谢和内分泌功能、器官和组织结构以及基因表达的改变。肾素-血管紧张素系统与内皮功能障碍的发生和动脉粥样硬化的进展密切相关。先前对胎儿编程的研究表明，肾素-血管紧张素系统关键基因的上调和血管紧张素 II 的作用增强。我们假设冠状脉管系统中肾素-血管紧张素系统的上调是胎儿编程的一个重要方面，导致氧化应激增加，最终导致冠状动脉内皮功能障碍和冠状动脉疾病。我们计划使用一种成熟的胎儿编程模型，即胎羊的早期产前暴露于地塞米松来进一步探索这一假设。由于环境对胎盘功能的影响而导致胎儿接触糖皮质激素的增加似乎是胎儿编程的重要机制。该提案的具体目的是证明产前接触地塞米松后，1) 冠状动脉血管紧张素 II 受体基因表达上调，2) 冠状血管反应性改变，特别是对血管紧张素的反应，3) 血管氧化应激增强， 4) 血管基因表达谱不同。我们认为这些差异在生命早期就存在，并在整个发展过程中持续存在。研究早期地塞米松暴露对冠状血管功能和血管基因表达的影响可能会提供不利的宫内环境与随后动脉粥样硬化发展之间的重要联系。了解这些联系以及胎儿环境改变导致成年后疾病的具体机制具有重要的全球公共卫生意义。只有在发展过程中了解高血压和心血管疾病的原因和机制，才有可能制定一级预防策略。