VASCULAR DISEASE IN HBP--ANGII, PAI1, INSULIN AND GENES

HBP 中的血管疾病——ANGII、PAI1、胰岛素和基因

• 批准号: 6044011
• 负责人: GORDON H WILLIAMS
• 金额: $ 46.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-14 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044011
• 关键词: ACE inhibitors; angiotensin II; angiotensinogen; atherosclerosis; clinical research; genetic polymorphism; genetic susceptibility; genotype; hemodynamics; human subject; hypertension; insulin sensitivity /resistance; kidney function; medical complication; myocardial ischemia /hypoxia; peptidyl dipeptidase A; phenotype; plasminogen activator; plasminogen activator inhibitors; renin angiotensin system

Cardiovascular mortality during the past three to four years has plateaued. Among the proposed reasons accounting for this is our limited knowledge of the interaction of the mechanisms enhancing cardiovascular risk. This proposal is designed to address three of these: 1) the renin-angiotensin system (RAS), 2) the plasminogen- activator-inhibitor-1 (PAI-1) system, and 3) the metabolic abnormalities associated with insulin resistance. We have documented potential links in abnormalities in these systems, which are likely to be genetically- determined. Specifically, 1) the RAS profoundly influences vascular response, renal function, and PAI-1 production. 2) An abnormality in the RAS is uniquely associated with insulin resistance. 3) Substantial variations in the occurrence of vascular (pressor, renal and atherosclerotic) and metabolic complications in the hypertensive population may be secondary to variations in the functions of critical genes. Thus, our overall hypothesis is: In hypertension, it is insulin resistance, with differences in the specific alleles of the genes of the RAS and PAI-1 system, that predispose to vascular complications. To evalulate this hypothesis, we will: 1) determine the relationship between insulin sensitivity and the RAS gene profile; 2) test the hypothesis that variation in the pressor and renal hemodynamic responses to angiotensin II (AngII) is mediated by variations in the genetic environment, specifically, the angiotensinogen (AGT) and angiotensin converting enzyme (ACE) genes; 3) assess the relationships between PAI-1 levels, insulin resistance, and the activity of the RAS, and correlate these with PAI-1 and RAS genotypes; and 4) determine the functional significance of polymorphism in the PAI-1 and RAS genes. To accomplish these goals, patients with hypertension will undergo a phenotyping protocol in a controlled environment. Then, mechanistic studies will explore the relationship between the pressor, renal hemodynamic, and PAI-1 responsiveness and the genotypes and insulin resistance. We anticipate that these studies will clarify 1) the relationship between abnormalities in the RAS and insulin resistance, 2) the role of the RAS in mediating the vascular and atherosclerotic (directly and via its effect on the PAI-1 production) complications of human hypertension, and 3) the likelihood that the genetic environment can explain the variable expression of these complications. With this information, specific preventive and therapeutic measures to retard the development of these complications could be proposed and tested in a clinical trial's format.

过去三四年来，心血管疾病死亡率 趋于稳定。 造成这种情况的拟议原因之一是我们 对增强机制的相互作用了解有限 心血管风险。 该提案旨在解决以下三个问题 这些：1）肾素-血管紧张素系统（RAS），2）纤溶酶原- 激活剂-抑制剂-1 (PAI-1) 系统，以及 3) 代谢异常 与胰岛素抵抗有关。 我们已经记录了潜在的联系 这些系统的异常可能是遗传性的 决定。 具体来说，1) RAS 深刻影响血管 反应、肾功能和 PAI-1 的产生。 2) 异常 RAS 与胰岛素抵抗有着独特的关联。 3）实质性 血管（升压、肾和）发生的变化 动脉粥样硬化）和高血压的代谢并发症 人口可能是关键功能变化的次要因素 基因。 因此，我们的总体假设是：在高血压中，胰岛素是关键 抗性，其基因的特定等位基因存在差异 RAS 和 PAI-1 系统，容易发生血管并发症。 为了评估这个假设，我们将：1）确定关系 胰岛素敏感性和 RAS 基因谱之间的关系； 2）测试 假设升压和肾脏血流动力学反应的变化 血管紧张素 II (AngII) 的变化是由遗传变异介导的 环境，特别是血管紧张素原（AGT）和血管紧张素 转换酶（ACE）基因； 3）评估PAI-1之间的关系 水平、胰岛素抵抗和 RAS 活性，并将其关联起来 这些具有 PAI-1 和 RAS 基因型； 4）确定功能 PAI-1 和 RAS 基因多态性的意义。 为了实现这些目标，高血压患者将接受 受控环境中的表型分析协议。那么，机械 研究将探讨升压、肾功能之间的关系 血流动力学、PAI-1 反应性以及基因型和胰岛素 反抗。 我们预计这些研究将澄清 1) RAS 异常与胰岛素抵抗之间的关系， 2）RAS在介导血管和动脉粥样硬化中的作用 （直接并通过其对 PAI-1 产生的影响）的并发症 人类高血压，以及 3) 遗传环境的可能性 可以解释这些并发症的变量表达。 有了这个 信息、具体的预防和治疗措施，以延缓疾病的发生 可以提出并测试这些并发症的发展 临床试验的形式。