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

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

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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）在心血管稳态和肾脏，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）的作用主要是通过内分泌和/或自分泌/旁分泌方式与AT1受体结合来介导的。我们和其他人最近确定了一种新型，内部或细胞内的ANG II介导作用模式，而不需要ANG II-AT1相互作用。我们报告说，心肌细胞在高葡萄糖条件下，将高水平的ANG II细胞内综合为细胞质和细胞核，而不会影响细胞质和细胞核。在高葡萄糖条件下的细胞内ANG II（IANG II）合成是Chymase，而不是血管紧张素转化酶（ACE）依赖性的。 ANG 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，糖尿病大鼠心脏的心脏明显增加了IANG II水平，心肌细胞凋亡，氧化应激和心脏纤维化，而不是通过肾素抑制，而不是通过ACE或AT1抑制。这些观察结果表明，IANG II在糖尿病心肌病中的重要作用，这意味着AT1受体拮抗剂和ACE抑制剂在阻断IANG II效应方面无效。在高葡萄糖条件下，导致RAS成分和ANG II合成的细胞内表达的细胞机制以及IANG II作用的机制尚不清楚。我们报告说，伊安（Iang II）会导致心脏肥大。然而，尚不清楚IANG II与细胞外ANG II在病理生理条件下的相对重要性。在该提案中，我们将检验以下假设：高葡萄糖引起的代谢变化导致ANG II的细胞内合成，该合成在糖尿病心肌病的发展中通过与新型细胞内蛋白质相互作用在发育中具有重要作用。我们将使用新生儿和成人的心肌细胞和成纤维细胞来鉴定高血糖诱导的细胞事件，例如六糖胺生物合成途径，蛋白O-糖基化和氧化应激，并通过药物学和遗传学方法调节细胞内Ras。我们将使用亲和力结合和质谱方法来识别并表征新型的IANG II相互作用蛋白。 AT1受体缺乏的小鼠将用于确定IANG II在糖尿病心脏功能障碍中的特定作用。拟议的研究将确定心脏中ANG II作用的新机制，并为糖尿病心肌病的临床干预提供新的策略。公共卫生相关性：这项研究将着重于制定糖尿病患者的新型策略。与具有血管紧张素受体阻滞剂和血管紧张素转化酶抑制剂的标准疗法相比，对细胞内肾素 - 血管紧张素系统的阻断可能为预防/治疗糖尿病心肌病的治疗提供了可观的好处。