Substrate Selection and Oxidative Stress in Heart Failure

心力衰竭的底物选择和氧化应激

• 批准号: 7750205
• 负责人: FABIO A RECCHIA
• 金额: $ 28.67万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750205
• 关键词: Address; Antioxidants; Area; Attenuated; Biochemical; Blood; Blood capillaries; Canis familiaris; Cardiac; Carnitine; Catecholamines; Cells; Coenzyme A; Cytopathology; DNA; Data; Data Analyses; Development; Dichloroacetate; Diet; Diffusion; Down-Regulation; Energy Metabolism; Enzyme Activation; Enzymes; Equilibrium; Esters; Failure; Fasting; Functional disorder; Gene Expression; Generations; Genes; Glucose; Glucose-6-Phosphate; Glucosephosphate Dehydrogenase; Glycolysis; Goals; Harvest; Heart; Heart failure; Hydrogen Peroxide; Hyperhomocysteinemia; Injury; Ischemia; Laboratories; Link; Manuscripts; Mass Spectrum Analysis; Measurement; Measures; Mechanics; Messenger RNA; Metabolic; Metabolism; Microarray Analysis; Mitochondria; Modeling; Molecular; Myocardial; Myocardium; NADP; NADPH Oxidase; Natural regeneration; Nitric Oxide Synthase; Nonesterified Fatty Acids; Oxidative Stress; Oxygen; Oxygen Consumption; Pentosephosphate Pathway; Perivascular Fibrosis; Phenotype; Physiological; Plasma; Play; Preparation; Production; Proteins; Protocols documentation; Pyruvate; Pyruvates; RNA; Reactive Oxygen Species; Reporter Genes; Role; Sampling; Simulate; Stress; Superoxides; System; Testing; Time; Tissue Sample; Tissues; Toxic effect; Tracer; Up-Regulation; Viral Vector; Work; activity marker; capillary; carbohydrate metabolism; density; electron donor; enzyme activity; fatty acid oxidation; gain of function; hemodynamics; in vivo; insight; instrument; interstitial; isoprostaglandin F2alpha type-III; knock-down; loss of function; medical schools; molecular marker; novel; overexpression; oxidation; oxidized low density lipoprotein; programs; research study; sugar

The failing heart displays an altered metabolic phenotype, characterized by downregulation of free fatty acid oxidation, enhanced glycolysis and glucose oxidation and impaired mitochondrial capacity for oxygen consumption and ATP generation. Whether these metabolic alterations are adaptive or maladaptive mechanisms and contribute to the progression from compensated to decompensated heart failure (HF) remain open questions. We have recently identified a potential link between increased carbohydrate metabolism and a major mechanism of cellular damage in the failing heart, namely oxidative stress. In decompensated HF, myocardial glucose-6-phosphate dehydrogenase (G6PDH) is upregulated and, consequently, more glucose is channeled into the oxidative pentose phosphate pathway. This leads to an increased synthesis of cytosolic NADPH, an electron donor normally utilized by cells to regenerate antioxidant systems, but that in the failing myocardium can fuel superoxide-producing enzymes such as NADPH oxidase and uncoupled NO synthase. We therefore provided the first evidence to suggest a cause- effect relationship linking enhanced glucose utilization, increased NADPH supply by upregulation of the pentose phosphate pathway and higher superoxide production in the failing heart. The overall goal of the present project is to test the hypothesis that HF increases myocardial flux of glucose into the oxidative pentose phosphate pathway, enhances NADPH supply to superoxide-generating enzymes, and accelerates oxidative stress and functional damage. Studies will be performed on chronically instrumented dogs with pacing-induced HF. Specific Aim #1 is to determine whether the altered substrate metabolism increases myocardial oxidative stress in HF. Circulating free fatty acids and glucose will be altered in healthy and HF dogs to simulate physiological conditions such as fasting and post-prandial state and to assess their effects on cardiac oxidative stress at baseline and during catecholamine stress. Specific Aim #2: is to determine whether the oxidative pentose phosphate pathway plays a critical role in fueling superoxide-generating enzymes in the failing heart. During development of HF, myocardial G6PDH will be knocked down by delivering DNA encoding for short interfering RNA and carried by viral vectors. Alternatively, G6PDH gene will be delivered via viral vectors to induce its overexpression. Specific Aim #3: is to determine whether the

衰竭的心脏表现出代谢表型的改变，其特征在于游离脂肪酸的下调 氧化，增强糖酵解和葡萄糖氧化以及受损的线粒体氧能力 消耗和ATP生成。这些代谢改变是适应性的还是不适应的 机制，并有助于从代偿性心力衰竭（HF）发展到失代偿性心力衰竭（HF） 仍然是悬而未决的问题。我们最近发现了碳水化合物增加 代谢和细胞损伤的主要机制，即氧化应激。在 在失代偿性HF中，心肌葡萄糖-6-磷酸脱氢酶（G6 PDH）上调， 因此更多的葡萄糖被导入氧化戊糖磷酸途径。这导致 增加胞质NADPH的合成，NADPH是一种通常被细胞用于再生的电子供体 抗氧化系统，但在失败的心肌可以燃料超氧化物产生酶， NADPH氧化酶和解偶联NO合酶。因此我们提供了第一个证据- 与葡萄糖利用增强、NADPH供应增加（通过上调 戊糖磷酸途径和更高的超氧化物产生在衰竭的心脏。的总体目标 目前的项目是检验HF增加心肌葡萄糖流入氧化心肌的假设。 戊糖磷酸途径，增强NADPH供应超氧化物生成酶，并加速 氧化应激和功能损伤。研究将在长期内固定犬中进行， 起搏诱导的HF。具体目标#1是确定改变的底物代谢是否增加 HF心肌氧化应激。在健康和HF患者中，循环游离脂肪酸和葡萄糖将发生改变。 狗模拟生理条件，如空腹和餐后状态，并评估其影响 对心脏氧化应激的影响。具体目标#2：确定 氧化戊糖磷酸途径是否在促进超氧化物生成中起关键作用 衰竭心脏中的酶在HF的发展过程中，心肌G6 PDH将被 递送编码短干扰RNA并由病毒载体携带的DNA。或者，G6 PDH基因 将通过病毒载体递送以诱导其过表达。具体目标#3：确定