ACE Balance in the Cardiovascular Complications of Diabetes

描述（由申请人提供）：心血管病变是胰岛素抵抗综合征最有害的结果，有证据表明它们与肾素血管紧张素系统（RAS）的紊乱有关。我们对胰岛素抵抗的饮食（果糖喂养）和遗传（瘦素受体突变，db/db）模型的研究表明，胰岛素升高，葡萄糖耐量降低和血压升高。我们推测心血管变化与产生血管紧张素II （Ang II）的血管紧张素转换酶（ACE）和产生Ang的ACE2之间的失衡有关（1-7）。数据记录了db/db小鼠血压和ACE/ACE2平衡的发育和年龄相关变化，以及果糖过载后ACE/ACE2的变化。我们计划利用一系列复杂的体内心血管试验，以及ACE活性的质谱（MS）测定、Ang肽形式的免疫测定、mRNA定量的分子方法和siRNA基因沉默，追踪胰岛素抵抗型糖尿病的病因和治疗。需要解决的问题是：1)胰岛素抵抗果糖模型中ACE/ACE2平衡变化的本质是什么？阻断RAS和Ang受体的作用是什么？2)胰岛素抵抗遗传db/db模型中ACE/ACE2平衡变化的本质是什么？阻断RAS和Ang受体的作用是什么？3) ACE/ACE2和Ang受体的基因调控对饮食诱导胰岛素抵抗的心血管和代谢反应有何影响？我们将使用过表达ACE的转基因小鼠和缺乏ACE2以及Ang受体shRNA基因沉默的小鼠。该研究计划将为与2型糖尿病实验模型相关的心血管病理的内分泌酶介质提供新的信息。公共卫生相关性：胰岛素抵抗性糖尿病是一个主要的健康问题，心血管功能障碍是死亡率和发病率的主要原因。该研究项目将研究胰岛素抵抗动物模型中心血管和代谢紊乱的发展。假设是肾素血管紧张素系统的变化，特别是血管紧张素转换酶的平衡，是一个关键因素。

DESCRIPTION (provided by applicant): Cardiovascular pathologies are the most deleterious outcomes of the insulin resistant syndrome and evidence links them to derangements in the renin angiotensin system (RAS). Our studies in dietary (fructose feeding) and genetic (leptin receptor mutant, db/db) models of insulin resistance show that there is increased insulin, impaired glucose tolerance and increased blood pressure (BP). We hypothesize that the cardiovascular changes are related to an imbalance between angiotensin converting enzyme (ACE) which produces angiotensin II (Ang II) and ACE2 which produces Ang (1-7). Data documents developmental, age-related changes in BP and ACE/ACE2 balance in db/db mice as well as changes in ACE/ACE2 after fructose overload. Using a sophisticated series of in vivo cardiovascular tests along with mass spectrometric (MS) assays for ACE activity, immunoassays for Ang peptide forms, molecular methods for mRNA quantification and siRNA gene silencing, we plan to follow the etiology and treatment of dietary and genetic forms of insulin resistant diabetes. The questions to be addressed are the following: 1) What is the nature of the changes in ACE/ACE2 balance in the fructose model of insulin resistance and what is the effect of blockade of the RAS and Ang receptors?; 2) What is the nature of the changes in ACE/ACE2 balance in the genetic db/db model of insulin resistance and what is the effect of blockade of the RAS and Ang receptors? and 3) What is the effect of genetic manipulation of ACE/ACE2 and Ang receptors on the cardiovascular and metabolic response to dietary induced insulin resistance? We will use transgenic mice which over- express ACE and mice which lack ACE2 as well as shRNA gene silencing for Ang receptors. The research program should provide new information on the endocrine enzymatic mediators of the cardiovascular pathologies associated with experimental models for type-2 diabetes. PUBLIC HEALTH RELEVANCE: Insulin resistant diabetes is a major health problem with cardiovascular dysfunction being a primary cause of mortality and morbidity. The proposed research project will study the development of cardiovascular and metabolic derangements in animal models of insulin resistance. The hypothesis is that changes in the renin angiotensin system, specifically angiotensin converting enzyme balance, are a key factor.