POLYOL PATHWAY & MECHANISMS OF ISCHEMIC INJURY IN AGING

多元醇途径

基本信息

批准号：
7796544
负责人：
Ravichandran Ramasamy
金额：
$ 21.72万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
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/7796544
关键词：
1,2-diacylglycerol 3-deoxyglucosone Address Adenine Nucleotides Advanced Glycosylation End Products Age Aging Aging-Related Process Aldehyde Reductase Animal Experimentation Animals Antigens Attenuated Biochemical Biometry Blood Vessels Breeding Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Death Cells Data Diabetes Mellitus Diglycerides Energy Metabolism Enzymes Exhibits Failure Fatty Acids Functional disorder Generations Glucose Glycolysis Goals Grant Heart Heart failure Homeostasis Human Impairment Incidence Infarction Injury Inner mitochondrial membrane Investigation Ischemia Kinetics Knockout Mice L-Iditol 2-Dehydrogenase Lead Light Link Mediating Membrane Messenger RNA Metabolic Metabolism Mitochondria Modeling Molecular Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardium NMR Spectroscopy Na(+)-K(+)-Exchanging ATPase Oxidative Phosphorylation Oxidative Stress Oxygen Consumption Pathway interactions Permeability Predisposition Principal Investigator Production Property Protein Isoforms Protein Kinase C Pyruvaldehyde Rattus Reactive Oxygen Species Recovery Recovery of Function Reperfusion Injury Reperfusion Therapy Resources Role Sodium Stress Swelling Techniques Testing Time Tissues Transgenic Mice Up-Regulation Work aged cofactor data management enzyme pathway fatty acid metabolism glucose metabolism heart function human subject improved in vivo inhibitor/antagonist inorganic phosphate insight meetings mitochondrial permeability transition pore mouse model overexpression oxidation polyol programs protein expression research study response to injury

项目摘要

Aging human subjects display increased incidence of cardiovascular disease and complications of myocardial infarction and heart failure. We have demonstrated that flux via the polyol pathway is partly responsible for impaired myocardial glycolysis and energy production. When hearts from aged rats are subjected to ischemia, the ability to generate sufficient high energy phosphates for maintaining myocyte viability and sodium homeostasis is severely compromised. Our work, as well as that of others, has shown that enhancement of glycolytic metabolism during ischemia is a feasible approach to maintain myocyte viability, energy metabolism and sodium homeostasis. In this revised application, we show that in human aging, that is, without superimposed cardiovascular disease or diabetes, and in aged Fischer 344 rats, expression and activity of aldose reductase (AR) is increased in the heart. Induction of ischemia further increases AR activity in aged hearts, and is associated with increased myocardial ischemic injury and poor functional recovery on reperfusion. Inhibition of the polyol pathway (AR) or the next enzyme in the pathway, sorbitol dehydrogenase (SDH) reduced ischemic injury, attenuated changes in intracellular sodium homeostasis, and improved functional and metabolic recovery after ischemia in aged hearts. Thus, we hypothesize that in aging, increased activity of the polyol pathway enzyme AR increases myocardial vulnerability to ischemic injury, and that this can be attenuated by polyol pathway inhibitors. The proposed studies will probe the mechanisms by which aging increases myocardial polyol pathway activity, and how this augmented activity in aging and ischemia acts to increase myocardial damage Distinct strategies including pharmacological inhibitors of AR and SDH, Fischer 344 rats, and human AR expressing transgenic mice will be employed to test these concepts. Further, to enhance understanding of SDH in aging in the heart, SDH null mice will be bred into the transgenic mouse background in which human-relevant levels of AR are expressing. We will utilize NMR spectroscopy, biochemical, and molecular techniques in our experiments. Project 1 is closely linked to Projects 2&3, as each studies aging-linked enhanced vulnerability to I/R stress in vascular cells and cardiomyocytes. Project 1 shares mouse/rat models with Projects 2 and 3. Project 1 will utilize all three Cores of the Program Project during all five years of the grant.

老龄化人类受试者心血管疾病和并发症的发病率增加心肌梗塞和心力衰竭。我们已经证明，通过多元醇途径的通量部分是负责心肌糖酵解和能量产生受损。当老年老鼠的心脏被遭受缺血时，产生足够的高能磷酸盐以维持肌细胞的能力活力和钠稳态受到严重损害。我们以及其他人的工作已经表明缺血期间增强糖酵解代谢是维持肌细胞的可行方法活力、能量代谢和钠稳态。在这个修订后的申请中，我们表明在人类中衰老，即没有叠加心血管疾病或糖尿病，在老年 Fischer 344 大鼠中，心脏中醛糖还原酶（AR）的表达和活性增加。进一步诱导缺血增加老年心脏的 AR 活性，并与心肌缺血性损伤增加和心脏功能不良有关再灌注时功能恢复。抑制多元醇途径 (AR) 或途径中的下一种酶，山梨醇脱氢酶 (SDH) 减少缺血性损伤，减弱细胞内钠的变化体内平衡，并改善老年心脏缺血后的功能和代谢恢复。因此，我们假设在衰老过程中，多元醇途径酶 AR 活性的增加会增加心肌易受缺血性损伤的影响，并且可以通过多元醇途径抑制剂来减弱这种损伤。拟议的研究将探讨衰老增加心肌多元醇途径活性的机制，以及如何这种在衰老和缺血中增强的活性会增加心肌损伤包括 AR 和 SDH 的药理学抑制剂、Fischer 344 大鼠和表达转基因的人 AR 将使用小鼠来测试这些概念。此外，为了增强对 SDH 在老龄化方面的理解心脏，SDH 缺失小鼠将被培育到转基因小鼠背景中，其中人类相关水平的 AR正在表达。我们将在我们的研究中利用核磁共振波谱、生化和分子技术实验。项目 1 与项目 2 和 3 密切相关，因为每个项目都研究与衰老相关的增强脆弱性血管细胞和心肌细胞的 I/R 应激。项目 1 与项目 2 和 3 共享小鼠/大鼠模型。项目 1 将在资助的所有五年内利用该计划项目的所有三个核心。