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) 会导致糖酵解增加、内部 pH 值变化、炎症和活性氧 (ROS) 水平升高，从而导致 I/R 损伤及其临床结果。然而，心肌I/R的一个常见生化特征是反应性羰基的形成增加，这些羰基在缺血心脏中大量产生，并且在再灌注时其浓度进一步增加。先前的研究表明，增加这些羰基的酶促解毒可减少心肌缺血再灌注损伤。然而，目前尚不清楚 I/R 过程中会产生哪些羰基以及它们如何导致组织损伤。因此，羰基化合物对心肌 I/R 损伤的一般贡献仍不清楚，并且尚未开发出特定的羰基猝灭干预措施来限制 I/R 损伤。当前的项目旨在了解心脏合成的内源性组氨酰二肽在预防缺血再灌注期间羰基毒性中的作用。肌肽和鹅肌肽等组氨酰二肽与结构多样的羰基发生强烈反应，我们认为这些肽代表了一般的羰基解毒途径。为了检验这一假设，我们将阐明组氨酰二肽在心肌缺血再灌注损伤中的作用。使用心肌 I/R 损伤的原位和离体模型，我们将检查通过组氨酰二肽合酶 (HDS) 在心脏中的过度表达或外源性递送来增加组氨酰二肽的心肌水平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解毒作用增加所致，我们将确定这些肽的心肌水平增加是否与羰基去除和排泄增加有关。我们的研究还将描述组氨酰二肽影响心肌 I/R 的机制受伤。具体来说，我们将检查I/R期间产生的组氨酰二肽是否抑制蛋白酶体并诱导内质网应激，以及组氨酰二肽通过防止蛋白质羰基化从而减轻蛋白酶体功能障碍和内质网应激来减少心肌损伤。最后，我们将检查内源性和合成的组氨酰二肽对抗心肌缺血再灌注损伤的相对功效。为此，我们将比较不同内源性组氨酰二肽及其合成类似物对抗羰基毒性的相对功效，并研究这些肽增强的羰基猝灭特性是否能更好地保护心肌 I/R 损伤。该项目的完成将导致对心脏中存在的新型抗氧化系统的识别和评估，以及该系统的成分（组氨酰肽，HDS）如何预防缺血损伤（羰基毒性）的关键特征。我们期望这些研究将导致介导 I/R 的特定羰基的鉴定 损伤，以及它们如何导致心肌损伤。这些发现可能会导致强有力且有效的干预措施的发展，这些干预措施可在临床上用于限制心脏以及其他组织的缺血和氧化损伤。