REGULATION OF THE PROCESSING ENZYMES OF ANGIOTENSIN (1-7)

血管紧张素I（AngI）可被加工成许多活性的 片段，其中血管紧张素II仍然是最广泛的研究。我们有 显示血管紧张素I可以被直接加工成另一种独特的产品- Ang-（1-7）-具有重要的作用，包括血管舒张， 利尿和利钠，刺激肾上腺素，增强 缓激肽的血管舒张作用和一氧化氮的释放。 Ang-（1-7）的这些作用和血管收缩剂、钠和 与Ang II相关的保水作用认为， Ang-（1-7）的表达可能会抵消Ang II的作用。支持 根据这一假设，我们发现抑制Ang-（1-7）的合成， I导致高血压反应，特别是在 盐耗尽或处于肾素慢性阻断下的动物- 血管紧张素系统（RAS）。此外，我们发现中性内肽酶 或脑啡肽酶（NEP）和血管紧张素转化酶（ACE）可以是 产生和代谢Ang-（1-7）的主要酶。主 本提案的目的是确定如何激活 RAS导致Ang-（1-7）的可变表达。本提案的目的是 是基于这样的假设，即NEP和ACE的调节将 影响血管内Ang（1-7）水平，对抗Ang（1-7）的作用 二.我们建议在低盐NEP上升的条件下- 调节以增加Ang-（1-7）的产生，而相反 ACE的变化也通过降解过程影响肽。 具体目标1将确定 ACE和NEP对Ang I和Ang-（1-7）的加工。具体目标2将 探讨低盐摄入对NEP和ACE的调节作用， 正常血压和高血压动物。第3章调查 NEP和ACE对主动脉内皮细胞的调节机制 细胞拟议的研究将提供一个新的理解， 调节控制表达的生化过程， RAS的组成部分。

Angiotensin I (Ang I) can be processed into a number of active fragments, of which Ang II remains the most widely studied. We have shown that Ang I can be processed directly into another unique product- Ang-(1-7)-which possesses important actions that include vasodilation, diuresis and natriuresis, stimulation of prostaglandins, potentiation of the vasodilator effects of bradykinin and the release of nitric oxide. These actions of Ang-(1-7) and the lack of vasoconstrictor, sodium and water retaining effects associated with Ang II argue that the production of Ang-(1-7) may counter-balance the actions of Ang II. In support of this hypothesis, we find that inhibition of Ang-(1-7) synthesis form Ang I results in a hypertensive response that is particularly revealed in animals that are salt depleted or under chronic blockade of the renin- angiotensin system (RAS). Moreover, we show that neutral endopeptidase or neprilysin (NEP) and angiotensin-converting enzyme (ACE) may be the predominant enzymes that generate and metabolize Ang-(1-7). The primary objective of this proposal will be to determine how activation of the RAS leads to variable expression of Ang-(1-7). The aims of this proposal are based on the hypothesis that regulation of NEP and ACE will influence the vascular levels of Ang (1-7) to oppose the actions of Ang II. We propose that under conditions such as low salt NEP is up- regulated to increase the generation of Ang-(1-7) while reciprocal changes in ACE also influence the peptide through a degradative process. Specific Aim 1 will establish the kinetic characterization of the processing of Ang I and Ang-(1-7) by ACE and NEP. Specific Aim 2 will explore the regulation of NEP and ACE under reduced salt intake in normotensive and hypertensive animals. Specific Aim 3 will investigate the mechanisms of the regulation of NEP and ACE in aortic endothelial cells. The proposed studies will provide a new understanding of the regulation of the biochemical processes that control expression of the components of the RAS.