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

胎儿编程中的新型血管紧张素-(1-7)内肽酶

• 批准号: 9036034
• 负责人: MARK C CHAPPELL
• 金额: $ 23.25万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036034
• 关键词: Address; Adrenal Glands; Adult; Aging; Angiotensin Receptor; Angiotensinogen; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Area; Attenuated; Baroreflex; Biological Assay; Bradykinin; Brain; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cause of Death; Cells; Chronic; Data; Detection; Development; Diabetes Mellitus; Drug or chemical Tissue Distribution; Elements; Endocrine system; Endopeptidases; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Enzymes; Equilibrium; Event; Exhibits; Fatty acid glycerol esters; Glucocorticoids; Growth; Heart; Heart failure; Human; Hypertension; Hypotension; Immune; Immunoblotting; Infant; Injury; Investigation; Kidney; Lead; Metabolic; Metabolism; Mitochondria; Neurotensin; Nitric Oxide; Nuclear; Oxidative Stress; Pancreas; Pathway interactions; Peptide Hydrolases; Peptide Metabolism; Peptides; Process; Prostaglandins; Proteins; Receptor, Angiotensin, Type 1; Regulation; Renin; Renin-Angiotensin System; Research; Role; Sheep; Sodium; Specificity; Testing; Therapeutic; Tissues; Vascular Diseases; Vasodilation; Water; analog; angiotensin I (1-7); base; blood pressure reduction; blood pressure regulation; cardiovascular health; clinically relevant; design; fetal programming; improved; in utero; inhibitor/antagonist; novel; novel strategies; novel therapeutic intervention; prevent; protective effect; public health relevance; young adult

 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.

 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包括高血压、心力衰竭、衰老、糖尿病、血管疾病和慢性肾损伤的过程的基础或促成。RAS在功能上可分为两个相反的通路-ACE-Ang II-血管紧张素1型受体（AT 1 R）轴和NEP/ACE 2-Ang-（1-7）-MasR轴。Ang-（1- 7）的作用减轻或拮抗Ang Ⅱ的有害作用。Ang-（1-7）降低血压，通过释放一氧化氮和肾上腺素诱导血管舒张，改善代谢功能，表现出有效的抗炎、抗生长和抗纤维化作用，减弱氧化应激并改善中枢心血管通路如压力感受器反射。降低的“Ang-（1-7）张力”可能与Ang II-AT 1 R轴的激活一样导致心血管病理学。我们最近鉴定了一种Ang-（1-7）内肽酶（A7-EP），其直接将Ang-（1-7）降解为无活性肽Ang-（1-4）。此外，A7-EP不代谢缓激肽、神经降压素或爱帕琳，表明肽酶的独特特异性。A7-EP活性在胎儿程序化动物（子宫内糖皮质激素暴露）的CSF中高3倍，这些动物表现出较高的血压、降低的压力反射功能和较低的Ang-（1-7）水平。这些新的发现导致了以下总体假设：独特的A7-EP通过脑和肾中Ang-（1 -7）至Ang-（1-4）的有效代谢而有助于内源性Ang-（1-7）张力。这一建议可能会发现新的治疗策略，阻断肽酶和增强内源性Ang-（1-7）紧张。