RAGE & ISCHEMIC STRESS IN AGING VASCULATURE

愤怒

• 批准号: 7348520
• 负责人: ANN MARIE SCHMIDT
• 金额: $ 19.61万
• 依托单位: COLUMBIA 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/7348520
• 关键词: 1,2-diacylglycerol; 3-deoxyglucosone; Accounting; Address; Advanced Glycosylation End Products; Age; Aging; Aldehyde Reductase; Animal Experimentation; Animals; Antigens; Attenuated; Biochemical; Biological Models; Biology; Biometry; Blood Circulation; Blood Vessels; Breeding; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cells; Data; Defense Mechanisms; Development; Diabetes Mellitus; Diglycerides; Dominant Negative Receptor; Dominant-Negative Mutation; Drug Metabolic Detoxication; Endothelial Cells; Environment; Enzymes; Event; Excision; Functional disorder; Generations; Genetic; Goals; Grant; Heart; Heart Mitochondria; Human; Hypertension; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Knockout Mice; Lactoylglutathione Lyase; Ligands; Link; Lipids; Mediating; Mediator of activation protein; Metabolic; Metabolic stress; Metabolism; Mitochondria; Modeling; Molecular; Mus; Mutant Strains Mice; Myocardium; Operative Surgical Procedures; Organism; Participant; Pathway interactions; Physiological reperfusion; Pilot Projects; Predisposition; Preproendothelin; Prevention strategy; Principal Investigator; Protein Kinase C; Proteins; Pyruvaldehyde; Rattus; Reagent; Relative (related person); Reperfusion Injury; Reperfusion Therapy; Research Personnel; Resources; Risk Factors; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staging; Stress; Testing; Therapeutic; Time; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Up-Regulation; Work; age related; aged; cell type; concept; data management; emergency service responder; enzyme pathway; gain of function; glycation; healthy aging; human subject; human tissue; hypercholesterolemia; inhibitor/antagonist; juvenile animal; middle age; mouse model; novel; oxidation; polyol; programs; promoter; receptor; receptor expression; receptor for advanced glycation endproducts; receptor upregulation; research study; response; transcription factor; young adult

Aging in human subjects is associated with heightened susceptibility to injury triggered by ischemia/reperfusion (I/R). Fundamental metabolic and biochemical changes occur in aging tissues in the basal state, and consequent to I/R. Aged human and Fischer 344 rat hearts display increased accumulation of Advanced Glycation Endproducts (AGEs), the products of nonenzymatic glycation/oxidation of proteins/lipids. AGEs may impart "gain of function" in the tissues by virtue of their ability to trigger signaling pathways, via Receptor for AGE (RAGE). In human aging, in the absence of overt cardiovascular disease or diabetes, increased expression/activity of the key polyol pathway enzyme aldose reductase (AR) occurs, leading to multiple metabolic disturbances, including generation of methylglyoxal (MG) and 3- deoxyglucosone (3-DG), precursors of AGEs. Aged human hearts, in the absence of cardiovascular disease or risk factors, display increased expression of RAGE antigen vs. young hearts. Our preliminary data reveal that myocardium of aged Fischer 344 rats (age, 24 mos), displays increased RAGE antigen compared to young rats (age, 4 months), particularly in endothelial cells (EC) and cardiomyocytes. Pharmacological blockade of RAGE in aged Fischer 344 rats attenuates I/R injury in the isolated perfused heart. Thus, we hypothesize that in aging, accumulation of AGEs upregulates expression of RAGE, thereby establishing basal dysfunction. Upon superimposed I/R, augmented ligand-RAGE mechanisms set the stage for enhanced biochemical and inflammatory stress and impairment in metabolism. Together, these forces converge to magnify I/R injury. We will test these concepts in aged Fischer 344 rats and RAGE mutant mice. These studies will be built on the premise that pharmacological blockade of RAGE may represent a potent strategy for the prevention of age-related cardiovascular dysfunction. Project 2 is closely linked to Projects 1&3, as each studies aging-linked enhanced vulnerability to I/R in the intact heart and isolated EC and cardiomyocytes, respectively. Project 2 shares mouse/rat models with Projects 1 and 3. Project 2 will utilize all three Cores of the Program Project during all five years of the grant.

人类受试者的衰老与受伤的敏感性增强有关 缺血/再灌注（I/R）。基本的代谢和生化变化发生在衰老的组织中 基础状态，并归功于I/R。老年人和菲舍尔344大鼠心脏显示出增加的积累 晚期糖基化最终产物（年龄），非酶糖化/氧化的产物 蛋白质/脂质。年龄可以通过触发信号传导的能力来赋予组织中的“功能获得” 途径，通过年龄的受体（愤怒）。在人类衰老中，在没有明显的心血管疾病或 糖尿病，关键多元途径酶还原酶（AR）的表达/活性增加，发生了 导致多种代谢紊乱，包括产生甲基甘氨酸（MG）和3-- 脱氧葡萄酮（3-DG），年龄的前体。在没有心血管的情况下，人类的心脏老化 疾病或危险因素，显示出愤怒抗原与年轻心脏的表达增加。我们的初步 数据表明，老化的Fischer 344只大鼠（年龄，24 MO）的心肌显示出愤怒抗原的增加 与年轻大鼠（年龄为4个月）相比，特别是在内皮细胞（EC）和心肌细胞中。 老年菲舍尔344只大鼠的药理学封锁了孤立灌注的I/R损伤 心。因此，我们假设在衰老中，年龄的积累上调了愤怒的表达，从而 建立基础功能障碍。叠加I/R后，增强的配体机构设置了舞台 为了增强新陈代谢的生化和炎症胁迫和损害。在一起，这些力量 收敛以放大I/R损伤。我们将在老年Fischer 344大鼠和愤怒突变体中测试这些概念 老鼠。这些研究将基于以下前提：愤怒的药理学封锁可能代表 预防与年龄相关的心血管功能障碍的有效策略。项目2与 项目1和3，随着每项研究与Intaint Intact和孤立的EC的I/R相关的衰老增强了I/R的脆弱性 和心肌细胞。项目2与项目1和3共享鼠标/老鼠模型。项目2将 在赠款的所有五年中，都利用该计划项目的所有三个核心。