POLYOL PATHWAY & MECHANISMS OF ISCHEMIC INJURY IN AGING

多元醇途径

• 批准号: 8042638
• 负责人: Ravichandran Ramasamy
• 金额: $ 22.15万
• 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/8042638
• 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

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.

衰老的人类受试者显示出心血管疾病的发生率增加 心肌梗塞和心力衰竭。我们已经证明了通过多元元通路的通量部分是 负责心肌糖酵解和能量产生受损。当老鼠的心脏是 受到缺血的作用，能够产生足够的高能磷酸盐来维持肌细胞 生存力和钠稳态受到严重损害。我们的工作以及他人的工作 缺血期间糖酵解代谢的增强是维持肌细胞的一种可行方法 活力，能量代谢和钠稳态。在此修订的应用中，我们表明在人类中 衰老，即没有叠加心血管疾病或糖尿病的衰老，以及年龄的Fischer 344只大鼠 醛糖还原酶（AR）的表达和活性在心脏中增加。进一步诱导缺血 衰老心脏的AR活性增加，并与心肌缺血性损伤增加有关 再灌注时功能恢复。抑制多元醇途径（AR）或途径中的下一个酶， 山梨糖醇脱氢酶（SDH）降低缺血性损伤，细胞内钠的变化减弱 体内稳态，并改善了老年心脏缺血后的功能和代谢恢复。因此，我们 假设在衰老中，多元型途径酶AR的活性增加会增加心肌 缺血性损伤的脆弱性，并且可以通过多元途径抑制剂减弱。提议 研究将探测衰老增加心肌多元型途径活性的机制，以及如何 这种增强的衰老和缺血行为中的活动以增加心肌损害不同的策略 包括AR和SDH的药理抑制剂，Fischer 344只大鼠以及表达转基因的人AR 小鼠将被用来测试这些概念。此外，以增强对SDH在衰老中的理解 心脏，SDH无效小鼠将繁殖到转基因小鼠背景中，其中与人类相关的水平 AR正在表达。我们将利用NMR光谱，生化和分子技术 实验。项目1与项目2和3密切相关，因为每项研究都与衰老的增强脆弱性相关 血管细胞和心肌细胞中的I/R胁迫。项目1与项目2和3共享鼠标/大鼠模型。 项目1将在赠款的所有五年内利用该计划项目的所有三个核心。