AR & AGE-RAGE IN AGING: IMPACT ON ENDOTHELIAL AND VASCULAR STRESS

人类受试者的衰老伴随着心血管和内皮细胞的不可避免的发展， 功能障碍，随着时间的推移，特别是随着并发症和叠加的衰老相关疾病的增加， 导致对缺血/再灌注（I/R）应激的高度脆弱性。为了回应批评，我们 开发并将该项目集中在老化心血管系统的两个关键组成部分上， 生物体的放大损伤，无论是先天的，并在I/R。这些研究与项目1和项目2密切相关 这个节目。首先，炎症的基础程度在老年脉管系统中增加，特别是在老年人中。 内皮细胞（EC）。第二，先天性心肌细胞功能障碍在衰老中发展。线粒体变成 随着年龄的增长，心肌细胞有缺陷，并增加活性氧（ROS）的产生， 削弱ATP的生成。这种基本的损伤现象促进了细胞死亡的增强 - 尤其是在I/R中。因此，在从老年动物中获得的EC和心肌细胞中， 这些发现背后的精确的信号转导和转录调节机制是必不可少的 在确定新的目标，以抑制不利的心血管老化和减少放大的脆弱性， I/R压力我们将探讨的假设，增加活动的多元醇酶AR在老化驱动器 增强AGE生成的机制，从而募集AGEs和随后的信号转导 在EC和心肌细胞中;我们预测的机制与心血管功能障碍有关。我们 提出，当老年生物体暴露于心脏中的叠加I/R应激时，AR增加， AGE-1信号放大炎症和应激介质的产生，这些介质加重了 老心脏以与项目1和2（完整心脏）高度协同的方式，分离的EC和心肌细胞 将用于探测信号转导和转录因子机制， 调节老年心脏的基础和I/R应激。项目3与项目1和项目2共享小鼠/大鼠模型。 项目3将在赠款的所有五年内使用计划项目的所有三个核心。

Aging in human subjects is accompanied by the inevitable development of cardiovascular and endothelial dysfunction, which, over time, especially as co-incident and superimposed aging-related disorders mount, leads to a heightened vulnerability to ischemia/reperfusion (I/R) stress. In response to the critique, we have developed and focused this project on two key components of aging cardiovasculature that prime the aged organism for amplified injury, both innately, and upon I/R. These studies are tightly coupled to Projects 1 & 2 of this Program. First, basal degrees of inflammation increase in aged vasculature, particularly in aged endothelial cells (EC). Second, innate cardiomyocyte dysfunction develops in aging. Mitochondria become defective in cardiomyocytes as they age and increase generation of reactive oxygen species (ROS), thereby impairing ATP generation. Such fundamental injury phenomena promote conditions for enhanced cell death - especially in I/R. Thus, in both EC and cardiomyocytes retrieved from aged animals, identification of the precise signal transduction and transcriptional regulation mechanisms underlying these findings is essential in identifying novel targets to suppress adverse cardiovascular aging and diminish the amplified vulnerability to I/R stress. We will probe the hypothesis that increased activity of the polyol enzyme AR in aging drives mechanisms that enhance generation of AGE, thereby recruiting RAGE and consequent signal transduction in EC and cardiomyocytes; mechanisms which we predict are linked to cardiovascular dysfunction. We propose that when aged organisms are exposed to superimposed I/R stress in the heart, increased AR and AGE-RAGE signaling amplify production of inflammatory and stress mediators that exaggerate injury in the aged heart. In a manner highly synergistic with Projects 1&2 (intact heart), isolated EC and cardiomyocytes from aged animals will be used to probe the signal transduction and transcription factor mechanisms that regulate basal and I/R stress in the aged heart. Project 3 shares mouse/rat models with Projects 1 and 2. Project 3 will utilize all three Cores of the Program Project during all five years of the grant.