Aging & Vulnerability to Ischemia: Pathways & Rescue

描述(申请人提供)：即使在考虑了与衰老相关的主要疾病之后，人类受试者心血管疾病倾向增加的主要因素也是年龄本身的增加。该计划项目组发现的发现突出了衰老生物学中的新概念：首先，心脏中多元醇途径酶(AR)的水平和活性增加，特别是在内皮细胞和心肌细胞中。AR的上调导致多种后果，包括二酰甘油(DAG)的产生和蛋白激酶C(PKC)的激活，以及晚期糖基化终产物(AGEs)的前体3-脱氧葡萄糖苷(3-DG)和甲基乙二醛(MG)的产生。其次，在健康的老年人、年轻人和Fischer 344大鼠的心脏中，AGEs的积累和高级糖基化终产物受体(RAGE)的表达增加，尤其是在内皮细胞和心肌细胞中。AGE与RAGE的相互作用与细胞和组织扰动以及组织损伤密切相关。我们的计划建立在这样的假设之上，即AR使组织老化，导致基础状态下放大的心血管功能障碍。当叠加I/R应激时，至少部分通过增强AGE生成和RAGE表达，增加的生化和分子信号放大老年心脏的损伤。我们将剖析这些通路在衰老和I/R应激中的影响和交叉，并确定在基础衰老和I/R应激心血管系统中调节促炎和血栓形成基因表达的关键信号通路。 这项拟议的计划将由三个独立但高度整合的项目组成，由一个在心血管生物学领域有着长期合作历史的项目负责人领导。项目1和2将分别探讨AR通路和RAGE在完整心脏中的作用。项目3将在分离的EC和心肌细胞中探测AR和RAGE。这些研究将解决以下问题：AR和RAGE在衰老中的基础调节是否启动了老年心脏，特别是内皮细胞和心肌细胞，使I/R应激引起的损伤放大？这些途径是单独的，还是结合在一起，在衰老过程中保护心血管的新靶点？拟议的计划项目将得到三个核心的支持：行政和生物统计学；动物实验和分析；转基因小鼠和动物管理。这些努力将阐明衰老与增强对I/R应激的脆弱性之间的联系，并有可能发现抑制衰老心血管系统I/R损伤的新的治疗干预措施。

DESCRIPTION (provided by applicant): Even after accounting for the major aging-associated diseases, the major factor underlying the enhanced propensity to cardiovascular diseases in human subjects is advancing age itself. Findings uncovered by this Program Project team highlight new concepts in the biology of aging: First, the level and activity of the polyol pathway enzyme aldose reductase (AR) is increased in heart, particularly in endothelial cells and cardiomyocytes. Multiple consequences ensue from upregulation of AR, including generation of diacylglycerol (DAG) and activation of Protein Kinase C (PKC); and production of 3 deoxyglucosone (3-DG) and methylglyoxal (MG), precursors of Advanced Glycation Endproducts (AGEs). Second, accumulation of AGEs and expression of Receptor for Advanced Glycation Endproducts (RAGE) is increased in healthy aged vs. young human and Fischer 344 rat hearts, especially in endothelial cells and cardiomyocytes. The interaction of AGE with RAGE is linked intimately to cellular and tissue perturbation and tissue injury. Our Program is built on the hypothesis that AR primes aged tissues for amplified cardiovascular dysfunction in the basal state. Upon superimposed I/R stress, at least in part via enhanced AGE generation and RAGE expression, increased biochemical and molecular signals amplify injury in the aged heart. We will dissect the influence and intersection of these pathways in aging and I/R stress, and determine the key signaling pathways that modulate expression of pro-inflammatory and prothrombotic genes in basal aging and I/R- stressed cardiovasculature. This proposed Program will consist of three independent but highly integrated projects, led by a team of project leaders with a long history of collaboration in cardiovascular biology. Projects 1 & 2 will probe the role of AR pathway and RAGE in the intact heart, respectively. Project 3 will probe AR and RAGE in isolated EC and cardiomyocytes. These studies will address the questions: does basal modulation of AR and RAGE in aging prime the aged heart and, particularly, in endothelial cells and cardiomyocytes, for magnified injury upon I/R stress? Are these pathways, alone, or in combination, novel targets for cardiovascular protection in aging? The proposed Program Project will be supported by three cores: Administrative and Biostatistics; Animal Experimentation and Analysis; and Transgenic Mouse and Animal Management. These endeavors will shed light on mechanisms linking aging to enhanced vulnerability to I/R stress, and, potentially, uncover new therapeutic interventions to suppress I/R injury in the aging cardiovascular system.