Novel Angiotensin-(1-7) Endopeptidase in Fetal Programming

 描述(申请人提供)：肾素-血管紧张素系统(RAS)是调节血压和水钠平衡的关键内分泌系统。RAS的不适当表达被认为是高血压、心力衰竭、衰老、糖尿病、血管疾病和慢性肾脏损伤等过程的基础或促进因素。RAS在功能上可分为两条相对的通路--ACE-Ang II-Ang-1型受体(AT1R)轴和NEP/ACE2-Ang-(1-7)-MASR轴。Ang-(1-7)的作用是减轻或拮抗Ang II的有害作用。Ang-(1-7)通过释放一氧化氮和前列腺素来降低血压，诱导血管扩张，改善代谢功能，显示出强大的抗炎、抗生长和抗纤维化作用，减轻氧化应激，改善中枢心血管通路，如压力感受器反射。Ang-(1-7)张力降低可能与Ang II-AT1R轴的激活一样导致心血管病变。我们最近发现了一种Ang-(1-7)内肽酶(A7-EP)，它能将Ang-(1-7)直接降解为失活肽Ang-(1-4)。此外，A7-EP不代谢缓激肽、神经降压素或apelin，这表明该肽酶具有独特的专一性。在血压较高、压力反射功能减弱和Ang-(1-7)水平较低的胎儿程序性动物(宫内糖皮质激素暴露)的脑脊液中，A7-EP活性高3倍。这些新的发现导致了一个全面的假设，即独特的A7-EP通过脑和肾脏中Ang-(1-7)到Ang-(1-4)的有效代谢来促进内源性Ang-(1-7)张力的形成。该提案可能会确定新的治疗策略，阻断肽酶并增强内源性Ang-(1-7)张力。

 DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) is a key endocrine system in the regulating blood pressure and water and sodium balance. Inappropriate expression of the RAS is thought to underlie or contribute to processes that comprise hypertension, heart failure, aging, diabetes, vascular diseases, and chronic renal injury. The RAS can be functionally partitioned into two opposing pathways - the ACE-Ang II-angiotensin type 1 receptor (AT1R) axis and the NEP/ACE2-Ang-(1-7)-MasR axis. The actions of Ang-(1- 7) ameliorate or antagonize the deleterious effects of Ang II. Ang-(1-7) lowers blood pressure, induces vasodilation via release of nitric oxide and prostaglandins, improves metabolic function, exhibits potent anti-inflammatory, anti-growth and anti-fibrotic actions, attenuates oxidative stress and improves central cardiovascular pathways such as the baroreflex. Reduced "Ang-(1-7) tone" may contribute to cardiovascular pathologies as much as activation of the Ang II-AT1R axis. We recently identified an Ang-(1-7) endopeptidase (A7-EP) that directly degrades Ang-(1-7) to the inactive peptide Ang-(1-4). Moreover, A7-EP did not metabolize bradykinin, neurotensin or apelin suggesting a unique specificity of the peptidase. A7-EP activity was 3-fold higher in the CSF of fetal-programmed animals (in utero glucocorticoid exposure) that exhibit higher blood pressure, reduced baroreflex function and lower Ang-(1-7) levels. These novel findings lead to the overall hypothesis that a unique A7-EP contributes to endogenous Ang-(1-7) tone through the efficient metabolism of Ang-(1-7) to Ang-(1-4) in the brain and kidney. The proposal may identify new therapeutic strategies that the block the peptidase and enhance endogenous Ang-(1-7) tone.