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

血管紧张素I(Ang I)可被加工成多种活性物质 片段，其中Ang II仍然是研究最广泛的。我们有 表明Ang i可以直接加工成另一种独特的产品- Ang-(1-7)-具有重要的作用，包括血管扩张， 利尿和利钠，前列腺素的刺激，增强 缓激肽的血管扩张作用和一氧化氮的释放。 Ang-(1-7)的这些作用以及缺乏血管收缩药、钠和 与Ang II相关的保水效应认为，产量 Ang-(1-7)可以平衡Ang II的行动。支持 这一假说，我们发现抑制Ang-(1-7)合成形成Ang I导致高血压反应，这一点在 缺盐或肾素长期受阻的动物- 血管紧张素系统(RAS)此外，我们还证明了中性内肽酶 或奈普利辛(NEP)和血管紧张素转换酶(ACE)可能是 产生和代谢血管紧张素-(1-7)的主要酶。初级阶段 这项提案的目标将是确定如何激活 RAS导致Ang-(1-7)的可变表达。这项提议的目的是 是基于对NEP和ACE的调控将 影响血管紧张素转换酶(1-7)的血管水平对抗血管紧张素转换酶的作用 II.我们建议在低盐等条件下，NEP上升- 调节以增加Ang-(1-7)的生成，同时相互 血管紧张素转换酶的变化也通过降解过程影响多肽。 具体目标1将建立 ACE和NEP对Ang I和Ang-(1-7)的处理。特定目标2将 盐摄入量减少对NEP和ACE调节作用的探讨 血压正常和高血压的动物。《特定目标3》将展开调查 NEP和ACE在主动脉内皮细胞中的调节机制 细胞。拟议的研究将提供一个新的理解 对控制基因表达的生化过程的调控 RAS的组件。

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.