Aging & Vulnerability to Ischemia: Pathways & Rescue

描述（由申请人提供）：即使在考虑了主要的与年龄相关的疾病之后，人类受试者心血管疾病倾向增加的主要因素是年龄本身。该项目团队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醛糖还原酶（AR）的水平和活性增加，特别是在内皮细胞和心肌细胞中。AR上调会导致多种后果，包括二酰基甘油（DAG）的生成和蛋白激酶C （PKC）的激活；3-脱氧葡萄糖（3- dg）和甲基乙二醛（MG）的生成，这是晚期糖基化终产物（AGEs）的前体。其次，age的积累和晚期糖基化终产物受体（Receptor for Advanced Glycation endproduct， RAGE）的表达在健康的老年人和Fischer 344大鼠的心脏中增加，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。我们的项目是建立在这样的假设之上的：AR使老化组织在基础状态下放大心血管功能障碍。在I/R叠加应激下，至少部分通过AGE生成和RAGE表达增强，增加的生化和分子信号放大了老年心脏的损伤。我们将分析这些通路在衰老和I/R应激中的影响和交集，并确定在基础衰老和I/R应激心血管中调节促炎和促血栓基因表达的关键信号通路。

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.