VASCULAR AND CARDIAC INJURY IN HYPERTENSIVE ANIMAL MODELS

高血压动物模型中的血管和心脏损伤

基本信息

批准号：
6110555
负责人：
PETER BRECHER
金额：
$ 32.8万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-01 至 2000-01-31
项目状态：
已结题

项目摘要

The major focus of this project is to utilize in vivo models, including genetically altered animals, to determine the role of the renin- angiotensin system and nitric oxide in provoking cardiac and vascular changes that occur in response to experimental hypertension. The first specific aim is to study the effects of hypertension on the pathogenesis of atherosclerosis in transgenic mice models that develop atherosclerosis spontaneously. These studies will assess cellular and extracellular responses in the aorta of apoE deficient mice that will be bred to combine genetic traits that predispose to hyperlipidemia and hypertension. The availability of "knockout" mice for apoE, which develop atherosclerotic lesions in a predictable temporal pattern, will facilitate development of animals that combine these hyperlipidemic traits with the alteration of genes thought to modulate blood pressure. The development of these hybrid mice will be performed in collaboration with Dr. Paigen using approaches outlined in her proposal. Pharmacological experiments will be performed in hyperlipidemic mice to determine the role of the nitric oxide generating systems and the renin-angiotensin system in the pathogenesis of atherosclerotic lesions. Experiments designed to determine mechanisms for the attenuation of atherosclerosis by anti-hypertensive drugs will be initiated. The second specific aim is to study the interrelationships between the renin-angiotensin system and nitric oxide (NO) on the development of cardiac injury during experimental hypertension. Both rats and mice which have been shown by us to develop rapid and extensive responses in both heart and aorta in response to angiotensin ll (ang II) infusion will be used as experimental models. The cardiac responses will be examined by biochemical and histological techniques, including the use of cell-specific markers for identification of cell types and stage of cell cycle, and biochemical methods that quantitatate selective changes in gene expression and cbemical composition of both arterial and cardiac lesions. The potential mechanisms involved in these responses will be dissected out by different approaches, including: a) selective use of vasoactive agonists and antagonists to separate the effects of ang II, NO and blood pressure on the process; b) the use of transgenic mice lacking selective receptors for either angiotensin or alpha-adrenergic receptors and mice with selective impairment in the immune system. An hypothesis to be tested is that cell growth and/or proliferation are regulated in part by opposing effects of ang II and NO. The potential participation of cytokines produces by macrophages and/or lymphocytes to the remodelling processes will be assessed.

该项目的主要重点是利用体内模型，包括遗传改变的动物，以确定肾素的作用血管紧张素系统和一氧化氮在引起心脏和血管中响应实验性高血压而发生的变化。第一个具体目的是研究高血压对发病机理的影响转基因小鼠模型中动脉粥样硬化的动脉粥样硬化自发。这些研究将评估细胞和细胞外 APOE缺乏小鼠主动脉的反应，将繁殖以组合易于高脂血症和高血压的遗传特征。这 apoE的“淘汰”小鼠的可用性，这些小鼠发展为动脉粥样硬化可预测的时间模式的病变将有助于发展结合这些高脂性特征与改变的动物被认为调节血压的基因。这些混合动力的发展将使用方法与Paigen博士合作进行小鼠在她的提议中概述了。药理实验将在高脂小鼠确定产生一氧化氮的作用系统和肾素 - 血管紧张素系统动脉粥样硬化病变。旨在确定机制的实验通过抗高血压药对动脉粥样硬化的衰减将是发起。第二个具体目的是研究相互关系在肾素 - 血管紧张素系统和一氧化氮（NO）之间实验性高血压期间心脏损伤的发展。两只老鼠和我们已经证明的小鼠发展快速而广泛对血管紧张素LL的心脏和主动脉的反应（ANG II）输注将用作实验模型。心脏反应将通过生化和组织学技术进行检查，包括使用用于鉴定细胞类型和阶段的细胞特异性标记细胞周期和生化方法，可定量选择性变化动脉和心脏的基因表达和CBEMICAL组成病变。这些反应所涉及的潜在机制将是通过不同的方法进行解剖，包括：a）选择性使用血管活性激动剂和拮抗剂分开Ang II的作用，无和血压在过程中； b）缺乏的转基因小鼠的使用血管紧张素或α-肾上腺素受体的选择性受体和在免疫系统中有选择性损害的小鼠。一个假设测试是细胞生长和/或增殖部分受到调节通过Ang II和No的相反影响。潜在参与细胞因子通过巨噬细胞和/或淋巴细胞产生重塑过程将进行评估。