Cardiac pathophysiology of histidyl dipeptides

组氨酰二肽的心脏病理生理学

• 批准号: 8853943
• 负责人: Shahid P Baba
• 金额: $ 51.26万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853943
• 关键词: Acrolein; Advanced Glycosylation End Products; Aerobic Exercise; Affect; Aldehyde Reductase; Amino Acids; Anserine; Antioxidants; Attenuated; Biochemical; Brain; Buffers; Cardiac; Cardiac Myocytes; Carnosine; Cause of Death; Clinical; Development; Dipeptides; Drug Metabolic Detoxication; Enzymes; Excision; Excretory function; Fructose; Functional disorder; Glutathione S-Transferase; Glyceraldehyde; Glycolysis; Heart; Heart Injuries; In Situ; Inflammation; Inflammatory; Injury; Intervention; Ischemia; Lead; Link; Lipids; Mediating; Mediator of activation protein; Membrane Lipids; Metabolic; Metals; Modeling; Mus; Myocardial; Myocardial Ischemia; Myocardial Reperfusion; Outcome; Pathway interactions; Peptides; Perfusion; Physiological; Process; Property; Proteins; Pyruvaldehyde; Reactive Oxygen Species; Recovery; Relative (related person); Reperfusion Injury; Reperfusion Therapy; Role; Skeletal Muscle; Stress; System; Testing; Therapeutic; Tissues; Toxic effect; Work; adduct; aldehyde dehydrogenases; analog; base; chelation; crosslink; design; effective intervention; effective therapy; link protein; multicatalytic endopeptidase complex; myocardial damage; myocardial infarct sizing; novel; overexpression; oxidation; prevent; protein aggregation; public health relevance; sugar

DESCRIPTION (provided by applicant): Myocardial ischemia and reperfusion (I/R) results in increased glycolysis, changes in internal pH, inflammation, and elevated levels of reactive oxygen species (ROS) that contribute to I/R injury and its clinical outcomes. However, a common biochemical feature of myocardial I/R is increased formation of reactive carbonyls, which are generated in high abundance in the ischemic heart and their concentration is further increased upon reperfusion. Previous work has shown that increased enzymatic detoxification of these carbonyls decreases myocardial I/R injury. Nevertheless, it remains unclear which carbonyls are generated during I/R and how they contribute to tissue injury. As a result the general contribution of carbonyls to myocardial I/R injury remains unclear and no specific carbonyl quenching interventions have been developed to limit I/R injury. The current project is designed to understand the role of endogenous histidyl dipeptides, synthesized by the heart, in preventing carbonyl toxicity during I/R. Histidyl dipeptides such as carnosine and anserine, react avidly with structurally-diverse carbonyls, we propose that these peptides represent a general carbonyl detoxification pathway. To test this hypothesis, we will elucidate the role of histidyl dipeptides in myocardial I/R injury. Using both in situ and ex vivo models of myocardial I/R injury, we will examine whether increasing myocardial levels of histidyl dipeptides, either by overexpression of histidyl dipeptide synthase (HDS) in the heart or exogenous delivery will diminish tissue injury. To assess whether the cardioprotective effects of these peptides are due to increased carbonyl detoxification, we will determine whether increased myocardial levels of these peptides are associated with increased carbonyl removal and excretion Our studies will also delineate the mechanism by which histidyl dipeptides affect myocardial I/R injury. Specifically, we will examine whether histidyl dipeptides generated during I/R inhibit the proteasome and induce ER stress and that histidyl dipeptides decrease myocardial damage by preventing protein carbonylation and thereby attenuating proteasomal dysfunction and ER stress. Finally, we will examine the relative efficacy of endogenous and synthetic histidyl dipeptides against myocardial I/R injury. For this we will compare the relative efficacy of differet endogenous histidyl dipeptides and their synthetic analogs against carbonyl toxicity and investigate whether enhanced carbonyl quenching properties of these peptides result in greater protection against myocardial I/R injury. Completion of this project will lead to the identificatio and assessment of a novel antioxidant system present in the heart, and how components of this system (histidyl peptides, HDS) prevent critical features of ischemia injury (carbonyl toxicity). We expect that these studies will lead to the identification of specific carbonyls that mediate I/R injury, and how they contribute to myocardial damage. These findings might lead to the development of robust and effective interventions that could be used clinically to limit ischemic and oxidative injury in the heart as well as in other tissues.

描述（由申请人提供）：心肌缺血和再灌注（I/R）导致糖酵解增加，内部pH值的变化，炎症的变化以及有助于I/R损伤及其临床结果的活性氧（ROS）水平升高。然而，心肌I/R的常见生化特征是增加反应性羰基的形成，这是缺血性心脏高丰度产生的，并且在再灌注后其浓度进一步增加。先前的工作表明，这些羰基的酶解毒增加会减少心肌I/R损伤。然而，目前尚不清楚在I/R期间产生哪些羰基以及它们如何促进组织损伤。结果，羰基对心肌I/R损伤的一般贡献尚不清楚，并且没有开发出特定的羰基淬火干预措施来限制I/R损伤。当前的项目旨在了解由心脏合成的内源性组二肽在I/R期间防止羰基毒性方面的作用。组二二肽（例如肌肽和anserine）与结构多样的羰基反应，我们建议这些肽代表了一般的羰基解毒途径。为了检验这一假设，我们将阐明组酰二肽在心肌I/R损伤中的作用。使用心肌I/R损伤的原位和离体模型，我们将检查心肌二肽的心肌水平是否通过过度表达心脏中内二肽合酶（HDS）或外源性递送是否会减少组织损伤。为了评估这些肽的心脏保护作用是否是由于羰基排毒增加引起的，我们将确定这些肽的心肌水平升高是否与羰基去除和排泄增加有关，我们的研究还将描述小组二肽影响心肌I/R损伤的机制。具体而言，我们将检查在I/R期间产生的组酰基二肽是否抑制蛋白酶体并诱导ER应激，并且组酰基二肽通过防止蛋白羰基化并从而减轻蛋白酶体功能障碍和ER应激，从而减少心肌损伤。最后，我们将检查内源性和合成组二肽对心肌I/R损伤的相对功效。为此，我们将比较不同内源性内源性组二二肽的相对疗效及其对羰基毒性的合成类似物，并研究了这些肽的羰基淬灭性能是否增强了这些肽的特性会导致对心肌I/R损伤的更大保护。该项目的完成将导致对心脏中存在的新型抗氧化剂系统的识别和评估，以及该系统的组件（组酰基肽，HDS）如何阻止缺血损伤的关键特征（羰基毒性）。我们预计这些研究将导致鉴定介导I/R的特定羰基 受伤以及它们如何促进心肌损伤。这些发现可能导致鲁棒和有效的干预措施的发展，这些干预措施可以在临床上用于限制心脏和其他组织中的缺血性和氧化性损伤。