Cellular Regulation of Angiotensin Converting Enzyme 2 (ACE2)

血管紧张素转换酶 2 (ACE2) 的细胞调节

基本信息

批准号：
7619089
负责人：
PATRICIA E GALLAGHER
金额：
$ 27.87万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7619089
关键词：
Adult Angiotensin II Angiotensinogen Angiotensins Animal Model Area Astrocytes Baroreflex Binding Biological Assay Brain Brain region Breeding Cardiac Cardiovascular system Cell Nucleus Cell Proliferation Cerebrospinal Fluid Chromatin Conditioned Culture Media Data Down-Regulation Electrophoretic Mobility Shift Assay Elements Endothelin-1 Environment Enzyme Kinetics Enzymes Equilibrium Extracellular Space Functional disorder Glial Fibrillary Acidic Protein Growth Inhibitors Heart Heart Rate Homologous Gene Hydrolysis Hypothalamic structure Infusion procedures Intercellular Fluid Kidney Knockout Mice Lead Link Losartan Luciferases Maps Measures Mediating Medulla Oblongata Messenger RNA Mitogen-Activated Protein Kinases Mitogens Molecular Neonatal Neurons Nuclear Organ Pathology Peptides Peptidyl-Dipeptidase A Peripheral Phenotype Platelet-Derived Growth Factor Play Process Production Proteins Publishing Rat Strains Rattus Regulation Regulatory Element Renin Renin-Angiotensin System Reporter Genes Research Research Personnel Role Secretory Vesicles Signal Pathway Slice Sprague-Dawley Rats Substrate Specificity Testis Tissues Transcriptional Regulation Transgenic Organisms United States Vasoconstrictor Agents Vasodilator Agents angiotensin I (1-7)base blood pressure regulation cell growth regulation chromatin immunoprecipitation deletion analysis design diabetic rat enzyme mechanism extracellular heart function in vivo inhibitor/antagonist interstitial programs promoter receptor relating to nervous system research study response transcription factor

项目摘要

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）：数十年的研究已将肾素 - 血管紧张素系统确立为血压，稳态和细胞增殖的主要调节剂。肾素 - 血管紧张素系统的作用是由肽血管紧张素II（ANG II）的相对作用（一种有效的血管收缩剂和有丝分裂原）以及血管紧张素 - （1-7）[Ang-（1-7）]，一种血管脱硫剂和生长抑制剂。血管紧张素转换酶2（ACE2）最近被确定为ACE的同源物，优先从ANG II中形成Ang-（1-7）。高血压大鼠肾脏中的ACE2表达降低表明其对Ang II与Ang-（1-7）的平衡的贡献。尽管ACE2最初位于心脏，肾脏和睾丸等外围器官中，但我们在来自新生儿和成人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鉴定了ACE2 mRNA和蛋白质。此外，我们证明了用ANG II治疗培养的神经元和星形胶质细胞导致ACE2 mRNA和蛋白质显着降低。在令人兴奋的新结果中，我们表明抑制ACE2降低了对心率的压力反射控制，这表明ACE2的调节和ANG II与Ang-（1-7）之比的变化对于血压的中心控制至关重要。我们建议ACE2充当大脑中ANG LL/ANG-（1-7）浓度平衡的主要调节剂。在特定的目标1中，我们将确定ANG II调节表达改变肽浓度改变的转基因大鼠大脑中的ACE2 mRNA和蛋白质，以及在这些大鼠中对心率的控制或抑制ACE2活性后的心率控制。特定目标2中的研究将集中于从培养的星形胶质细胞分泌的ACE2，以评估其底物特异性并确定来自培养的星形胶质细胞和神经元以及完整脑切片的ACE2分泌的分子机制。最后，在特定的目标3中，我们将确定星形胶质细胞和神经元中ACE2的转录调节剂。相关性：ACE2优先将ANG II转换为ANG-（1-7），在血压中心控制中具有相反作用的肽。 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。