Novel Aspects of the Cardiac Renin-Angiotensin System

心脏肾素-血管紧张素系统的新方面

基本信息

批准号：
7729889
负责人：
KENNETH Melvin BAKER
金额：
$ 31.5万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-17 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729889
关键词：
AGTR2 gene Adult Affect Affinity Affinity Chromatography Anabolism Angiotensin II Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Animal Model Antibodies Apoptosis Binding Binding Proteins Binding Sites Biological Blood Vessels Cardiac Cardiac Myocytes Cardiovascular system Catheterization Cell Nucleus Cells Characteristics Chinese Hamster Ovary Cell Chymase Clinical Clinical Trials Co-Immunoprecipitations Column Chromatography Complications of Diabetes Mellitus Cytoplasm Data Development Diabetes Mellitus Disease Echocardiography Endocrine Event Fibroblasts Fibrosis Figs - dietary Functional disorder Gene Components Gene Expression Gene Proteins Genetic Glucose Glycolysis Heart Heart Diseases Heart Hypertrophy Hexosamines Homeostasis Human Hyperglycemia In Vitro Inactive Renin Intervention Kidney Knockout Mice Label Lead Left Life Mass Spectrum Analysis Measurement Mediating Meta-Analysis Metabolic Mus Muscle Cells Neonatal Nuclear Oxidative Stress Pathology Pathway interactions Patients Peptides Peptidyl-Dipeptidase A Phosphorylation Prevention Probability Protein Biosynthesis Pathway Protein Glycosylation Proteins Radiolabeled Rattus Regulation Relative (related person)Renin Renin-Angiotensin System Reporting Research Role Sepharose Smooth Muscle Myocytes Sodium Chloride Source Sp1 Transcription Factor Specificity Streptozocin Structure System TP53 gene Testing Time Ventricular Water analog autocrine base diabetic diabetic cardiomyopathy diabetic patient diabetic rat extracellular glycosylation in vivo inhibitor/antagonist kidney vascular structure mesangial cell non-diabetic novel novel strategies paracrine promoter protein expression public health relevance radiotracer receptor research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): The renin angiotensin system (RAS) has a central role in cardiovascular homeostasis and development of renal, vascular, and cardiac pathologies. The effects of angiotensin II (Ang II) are primarily mediated by binding to AT1 receptor in an endocrine and/or autocrine/paracrine manner. We and others have recently identified a novel, intracrine or intracellular, mode of Ang II-mediated actions that do not require Ang II-AT1 interaction. We reported that cardiac myocytes synthesize high levels of Ang II intracellularly, which redistributes to cytoplasm and nucleus, without affecting extracellular levels, in high glucose conditions. Intracellular Ang II (iAng II) synthesis in high glucose conditions is chymase, not angiotensin converting enzyme (ACE) dependent. Intracellular synthesis of Ang II is completely blocked by a renin inhibitor. We have also observed activation of the intracellular RAS in cardiac fibroblasts. Significantly, iAng II levels, cardiac myocyte apoptosis, oxidative stress, and cardiac fibrosis are markedly increased in the heart of diabetic rats, which are normalized by renin inhibition, not by ACE or AT1 inhibition. These observations suggest a significant role of iAng II in diabetic cardiomyopathy, with the implications that AT1 receptor antagonists and ACE inhibitors would be ineffective in blocking iAng II effects. The cellular mechanisms that lead to intracellular expression of RAS components and Ang II synthesis, in high glucose conditions, and the mechanism of iAng II actions are not known. We have reported that iAng II causes cardiac hypertrophy; however, the relative significance of iAng II versus extracellular Ang II in pathophysiological conditions is not known. In this proposal, we will test the hypothesis that metabolic changes, induced by high glucose, result in intracellular synthesis of Ang II, which has a significant role in development of diabetic cardiomyopathy, through interaction with novel intracellular proteins. We will use cardiac myocytes and fibroblasts, both neonatal and adult, to identify hyperglycemia-induced cellular events, such as the hexosamine biosynthesis pathway, protein O-glycosylation and oxidative stress, on regulation of the intracellular RAS, by pharmacological and genetic approaches. We will identify and characterize novel iAng II interacting proteins, using affinity binding and mass spectrometry approaches. AT1 receptor deficient mice will be utilized to determine the specific role of iAng II in diabetic cardiac dysfunction. The proposed studies will identify novel mechanisms of Ang II actions in the heart and provide for new strategies in clinical interventions for diabetic cardiomyopathy. PUBLIC HEALTH RELEVANCE: This research will focus on the development of novel strategies for the treatment of patients with diabetes. Blockade of the intracellular renin-angiotensin system, may provide substantial benefit for the prevention/treatment of diabetic cardiomyopathy, compared to standard therapy with angiotensin receptor blockers and angiotensin converting enzyme inhibitors.

描述（由申请人提供）：肾素血管紧张素系统（RAS）在心血管稳态以及肾脏、血管和心脏病理的发展中具有核心作用。血管紧张素 II (Ang II) 的作用主要是通过以内分泌和/或自分泌/旁分泌方式与 AT1 受体结合介导的。我们和其他人最近发现了一种新的、分泌内或细胞内的 Ang II 介导的作用模式，不需要 Ang II-AT1 相互作用。我们报道，在高葡萄糖条件下，心肌细胞在细胞内合成高水平的 Ang II，并重新分配到细胞质和细胞核，而不影响细胞外水平。高葡萄糖条件下细胞内血管紧张素 II (iAng II) 的合成依赖于食糜酶，而不依赖于血管紧张素转换酶 (ACE)。血管紧张素II的细胞内合成被肾素抑制剂完全阻断。我们还观察到心脏成纤维细胞中细胞内 RAS 的激活。值得注意的是，糖尿病大鼠心脏中 iAng II 水平、心肌细胞凋亡、氧化应激和心脏纤维化显着增加，这些通过肾素抑制而不是通过 ACE 或 AT1 抑制而正常化。这些观察结果表明 iAng II 在糖尿病性心肌病中发挥着重要作用，这意味着 AT1 受体拮抗剂和 ACE 抑制剂无法有效阻断 iAng II 的作用。在高葡萄糖条件下导致 RAS 成分细胞内表达和 Ang II 合成的细胞机制以及 iAng II 的作用机制尚不清楚。我们已经报道 iAng II 会导致心脏肥大；然而，iAng II 与细胞外 Ang II 在病理生理条件下的相对意义尚不清楚。在本提案中，我们将检验以下假设：高葡萄糖诱导的代谢变化会导致 Ang II 的细胞内合成，通过与新型细胞内蛋白质相互作用，Ang II 在糖尿病心肌病的发展中发挥重要作用。我们将使用新生儿和成人的心肌细胞和成纤维细胞，通过药理学和遗传学方法来识别高血糖诱导的细胞事件，例如己糖胺生物合成途径、蛋白 O-糖基化和氧化应激，以及细胞内 RAS 的调节。我们将使用亲和结合和质谱方法来鉴定和表征新型 iAng II 相互作用蛋白。 AT1 受体缺陷小鼠将用于确定 iAng II 在糖尿病心脏功能障碍中的具体作用。拟议的研究将确定 Ang II 在心脏中作用的新机制，并为糖尿病心肌病的临床干预提供新策略。公共健康相关性：这项研究将重点关注开发治疗糖尿病患者的新策略。与血管紧张素受体阻断剂和血管紧张素转换酶抑制剂的标准治疗相比，细胞内肾素-血管紧张素系统的阻断可为糖尿病心肌病的预防/治疗提供实质性益处。