Cellular Regulation of Angiotensin Converting Enzyme 2

血管紧张素转换酶 2 的细胞调节

• 批准号: 7147150
• 负责人: PATRICIA E GALLAGHER
• 金额: $ 28.7万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147150
• 关键词: angiotensin II; angiotensins; astrocytes; baroreflex; biological signal transduction; brain metabolism; brain stem; cerebrospinal fluid; chemical kinetics; chromatin immunoprecipitation; enzyme activity; enzyme substrate; gel mobility shift assay; genetic promoter element; glial fibrillary acidic protein; laboratory rat; neurochemistry; neuroregulation; peptidyl dipeptidase A; renin angiotensin system; reporter genes; secretion; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Decades of research have established the renin-angiotensin system as a major regulator of blood pressure, homeostasis, and cell proliferation. Renin-angiotensin system effects are mediated by the opposing actions of the peptides angiotensin II (Ang II), a potent vasoconstrictor and mitogen, and angiotensin-(1-7) [Ang-(1- 7)], a vasodilator and growth inhibitor. Angiotensin-converting enzyme 2 (ACE2) recently was identified as a homologue of ACE that preferentially forms Ang-(1-7) from Ang II. Reduced ACE2 expression in the kidney of hypertensive rats suggests its contribution to the balance of Ang II to Ang-(1-7). Although ACE2 was initially localized in peripheral organs such as heart, kidney and testis, we identified ACE2 mRNA and protein in distinct brain regions from both neonatal and adult Sprague-Dawley rats as well as cultured neurons and astrocytes. Further, we demonstrated that treatment of cultured neurons and astrocytes with Ang II caused a marked reduction in ACE2 mRNA and protein. In exciting new results, we showed that inhibition of ACE2 reduced baroreflex control of heart rate, suggesting that the regulation of ACE2 and alterations in the ratio of Ang II to Ang-(1-7) is critical in central control of blood pressure. We propose that ACE2 serves as a major regulator of the balance of Ang ll/Ang-(1-7) concentration in the brain. In Specific Aim 1, we will ascertain whether Ang II regulates ACE2 mRNA and protein in the brain of transgenic rats expressing altered peptide concentrations and whether baroreflex control of heart rate is altered in these rats or following inhibition of ACE2 activity. Studies in Specific Aim 2 will focus on ACE2 secreted from cultured astrocytes, to assess its substrate specificity and determine the molecular mechanism of ACE2 secretion from cultured astrocytes and neurons and from intact brain slices. Finally, in Specific Aim 3, we will identify the transcriptional regulators of ACE2 in astrocytes and neurons. Relevance: ACE2 preferentially converts Ang II to Ang-(1-7), peptides which have opposing actions in the central control of blood pressure. The regulation of ACE2 may be critical to maintaining the normal function of the renin-angiotensin system in the brain.

描述（由申请人提供）：数十年的研究已经确定肾素-血管紧张素系统是血压、体内平衡和细胞增殖的主要调节剂。肾素-血管紧张素系统作用是由肽血管紧张素 II (Ang II)（一种有效的血管收缩剂和有丝分裂原）和血管紧张素-(1-7) [Ang-(1-7)]（一种血管舒张剂和生长抑制剂）的相反作用介导的。血管紧张素转换酶 2 (ACE2) 最近被鉴定为 ACE 的同系物，优先从 Ang II 形成 Ang-(1-7)。高血压大鼠肾脏中 ACE2 表达的减少表明其有助于 Ang II 与 Ang-(1-7) 的平衡。尽管 ACE2 最初定位于心脏、肾脏和睾丸等外周器官，但我们在新生和成年 Sprague-Dawley 大鼠以及培养的神经元和星形胶质细胞的不同大脑区域中发现了 ACE2 mRNA 和蛋白质。此外，我们证明用 Ang II 处理培养的神经元和星形胶质细胞会导致 ACE2 mRNA 和蛋白质显着减少。在令人兴奋的新结果中，我们发现抑制 ACE2 会降低心率的压力反射控制，这表明 ACE2 的调节和 Ang II 与 Ang-(1-7) 比例的改变对于血压的中枢控制至关重要。我们认为ACE2是大脑中Ang 11/Ang-(1-7)浓度平衡的主要调节剂。在具体目标 1 中，我们将确定 Ang II 是否调节表达改变的肽浓度的转基因大鼠大脑中的 ACE2 mRNA 和蛋白质，以及在这些大鼠中或在抑制 ACE2 活性后，压力反射对心率的控制是否发生改变。具体目标 2 的研究将重点关注培养的星形胶质细胞分泌的 ACE2，评估其底物特异性并确定培养的星形胶质细胞和神经元以及完整脑切片分泌 ACE2 的分子机制。最后，在具体目标 3 中，我们将鉴定星形胶质细胞和神经元中 ACE2 的转录调节因子。相关性：ACE2 优先将 Ang II 转化为 Ang-(1-7)，这些肽在血压的中央控制中具有相反的作用。 ACE2的调节对于维持大脑中肾素-血管紧张素系统的正常功能可能至关重要。