Angiotensin-(1-12). Novel Pathways for Angiotensin Peptide Formation

血管紧张素-(1-12)。

• 批准号: 9247028
• 负责人: CARLOS M FERRARIO
• 金额: $ 13.37万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9247028
• 关键词: Accounting; Address; Adult; Affinity; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Antihypertensive Agents; Arrhythmia; Biochemical; Blood Circulation; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Chest; Chronic Kidney Failure; Chymase; Cleaved cell; Clinical Research; Clinical Trials; Clinical assessments; Diabetes Mellitus; Enzymes; Family member; Fibrosis; Fistula; Generations; Genes; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hormonal; Human; Hypertension; Injury; Kininogenase; Knowledge; Lead; Mechanics; Mediating; Metabolic Biotransformation; Metabolism; Modeling; Muscle Cells; Outcome; Outcome Assessment; Pathologic; Pathway interactions; Patients; Peptides; Physiology; Pilot Projects; Plasma; Process; Production; Rattus; Regulation; Renin; Renin-Angiotensin System; Reporting; Rodent; Role; Site; Species Specificity; Sprague-Dawley Rats; Stress; Stretching; Therapeutic; Tissues; Transgenic Organisms; Urine; Work; autocrine; base; clinically relevant; constriction; conventional therapy; coronary fibrosis; drug development; hemodynamics; in vivo; inhibitor/antagonist; interstitial; mast cell; novel; novel therapeutic intervention; overexpression; paracrine; pressure; receptor; response; species difference

Project Summary/Abstract - Project 1 Increased cardiac Ang II activity-as a result of upregulated Ang II formation in the intracellular or interstitial compartment acting via autocrine or paracrine mechanisms- contributes to cardiac hypertrophic remodeling, arrhythmias, and fibrosis. RAS inhibitors are less effective in blocking Ang II-mediated adverse cardiac remodeling because Ang II production in cardiac myocytes follows a non-canonical pathway through the processing of angiotensinogen (Aogen) into the dodecapeptide intermediate substrate Ang-(1-12). We further showed that Ang-(1-12) metabolism between rodents and humans is that chymase but not ACE converts Ang- (1-12) directly into Ang II in human heart tissue and that this process may include an additional step in which human Aogen may be processed into a newly identified precursor Ang-(1-25) prior to conversion into Ang-(1- 12). The human form of � cardiac chymase, either expressed in cardiomyocytes or incorporated into these cells from activated mast cells, is the enzyme producing Ang II from Ang-(1-12) and likely Ang-(1-25). Pilot studies suggest a role for kallikrein as the enzyme cleaving Ang-(1-12) from Aogen. On these bases, Project 1 poses the hypothesis that Ang II-mediated adverse cardiac remodeling results from the processing of intermediate forms of Aogen-derived peptides through the hydrolytic activity of intracellularly formed or incorporated chymase. Furthermore, we propose that these biotransformation steps are species-specific. To achieve these objectives we will determine: Aim 1, the compartmentalization and role of kallikrein or a kallikrein family member enzyme in the production of Ang-(1-12) from cardiac Aogen in WKY and SHR and its potential hydrolytic activity in cardiac Ang-(1-12) production in a transgenic rat model expressing the genes from human Aogen [TGR(hAGT)L1623]; Aim 2, the role of Ang-(1-12) and Ang-(1-25) as substrates for cardiomyocyte Ang II production in WKY and SHR versus TGR(hAGT)L1623 rats; Aim 3, the hemodynamic and RAS profile and the enzymes accounting for the expression of Ang-(1-25) and Ang-(1-12) in TGR(hAGT)L1623. We will also assess whether the chymase-driven cardiac Ang II pathway is influenced by species-specificity through the crossing of the human Aogen transgenic rat with a rat expressing the genes for human chymase. Our work will reveal new therapeutic approaches to hypertensive cardiac hypertrophy and fibrosis that are based on non- canonical cardiac Ang II formation.

项目概要/摘要-项目1 心脏Ang II活性增加--由于细胞内或间质中Ang II形成上调 隔室通过自分泌或旁分泌机制起作用-有助于心脏肥大性重塑， 心律失常和纤维化RAS抑制剂在阻断Ang II介导的不良心脏反应方面效果较差 由于心肌细胞中的Ang II产生遵循非经典途径， 将血管紧张素原（Aogen）加工成十二肽中间底物Ang-（1 - 12）。我们进一步 显示，在啮齿动物和人类之间的Ang-（1 - 12）代谢是糜酶而不是ACE将Ang-（1 - 12）转化为 （1 - 12）直接转化为人心脏组织中的Ang II，并且该过程可以包括另外的步骤，其中 人Aogen可以在转化成Ang-（1 - 25）之前加工成新鉴定的前体Ang-（1 - 25）。 12）。人型心肌糜酶，在心肌细胞中表达或被整合到心肌细胞中。 来自活化肥大细胞的细胞，是从Ang-（1 - 12）和可能的Ang-（1 - 25）产生Ang II的酶。试点 研究表明激肽释放酶作为切割来自Aogen的Ang-（1 - 12）的酶的作用。在此基础上，项目1 提出了一个假设，即血管紧张素II介导的不良心脏重塑的结果，从处理 Aogen衍生肽的中间形式通过细胞内形成的或 并入的糜酶。此外，我们认为这些生物转化步骤是物种特异性的。到 为了实现这些目标，我们将确定：目标1，激肽释放酶或激肽释放酶的区室化和作用 WKY和SHR心肌组织Ang-（1 - 12）产生的家族成员酶及其潜力 在表达人源基因的转基因大鼠模型中心脏Ang-（1 - 12）产生的水解活性 Aogen [TGR（hAGT）L1623];目的2，Ang-（1 - 12）和Ang-（1 - 25）作为心肌细胞Ang-（1 - 12）和Ang-（1 - 25）的底物的作用 WKY和SHR与TGR（hAGT）L1623大鼠的II产生;目的3，血流动力学和RAS特征， 负责TGR（hAGT）L1623中Ang-（1 - 25）和Ang-（1 - 12）表达的酶。我们还将 评估凝乳酶驱动的心脏血管紧张素II通路是否受到物种特异性的影响， 将人Aogen转基因大鼠与表达人糜酶基因的大鼠杂交。我们的工作将 揭示了新的治疗方法，高血压心脏肥大和纤维化的基础上，非- 典型的心脏血管紧张素II形成。