Hexosamine biosynthesis pathway metabolism during cardiac hypertrophy

心脏肥大期间己糖胺生物合成途径代谢

• 批准号: 10586575
• 负责人: Aaron K Olson
• 金额: $ 75.08万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-20 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586575
• 关键词: Address; Affect; Anabolism; Animal Model; Animals; Aorta; Aortic Valve Stenosis; Aortic coarctation; Cardiac; Cardiovascular Diseases; Cessation of life; Citric Acid Cycle; Clinical; Data; Disease; Energy-Generating Resources; Enzymes; Equilibrium; Evaluation; Fatty Acids; Generations; Glucose; Glutamine; Glycolysis; Goals; Growth; Heart; Heart Hypertrophy; Heart failure; Hexosamines; Human; Hypertension; Hypertrophy; Knock-out; Knowledge; Left Ventricular Function; Link; Measures; Mediating; Metabolic; Metabolism; Methods; Modification; Myocardial dysfunction; Organ; Outcome; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Pilot Projects; Post-Translational Protein Processing; Production; Protein Isoforms; Proteins; Regulation; Role; Source; Stenosis; Stress; Testing; Therapeutic; Transgenic Mice; Ventricular Dysfunction; Ventricular Remodeling; aorta constriction; disability; enzyme pathway; experimental study; fatty acid oxidation; fructose-6-phosphate; glucose metabolism; heart function; heart metabolism; improved; insight; novel therapeutic intervention; novel therapeutics; overexpression; oxidation; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; preference; preservation; pressure; prevent; response; structural heart disease; targeted treatment

PROJECT SUMMARY A broad range of diseases, from hypertension to structural heart diseases like aortic stenosis or coarctation of the aorta, cause pressure overload stress on the heart. In response, the heart undergoes hypertrophy (called pressure overload hypertrophy or POH) which can promote adaptation or cause heart failure. Understanding the mechanism underlying these opposite clinical outcomes would create new therapeutic opportunities. The unstressed heart relies mainly on fatty acids for fuel but alters energy sources depending on availability. POH causes the heart to increase its reliance on glucose for energy, but, unfortunately, this metabolic inflexibility impacts hypertrophic growth and ventricular dysfunction. Therefore, improving the balance of sources used for fuel generation during POH could promote adaptation but therapies targeting this approach have not been realized partially because the mechanisms underlying these metabolic changes are incompletely known. Our preliminary results identified a new mechanism potentially impacting substrate preferences for energy production in the citric acid cycle during POH that we pursue in this proposal. Posttranslational modifications by O-linked β-N-acetylglucosamine (O-GlcNAc) globally increase in hypertrophied hearts in humans and animals. A widely accepted dogma assumes that the hexosamine biosynthesis pathway (HBP) leading to the O-GlcNAcylation of proteins depends on metabolic changes, especially in glycolytic flux. However, our recent data suggests the reverse; that HBP flux and O-GlcNAc levels determine cardiac fuel utilization. We recently performed the most comprehensive evaluation of protein O-GlcNAc changes during POH and preliminarily identified increased O-GlcNAc levels on multiple enzymes for fatty acids and glucose metabolism. Accordingly, we propose a new paradigm that HBP flux and O-GlcNAc are key regulators of fuel preferences for the citric acid cycle during POH. Thus, O-GlcNAc could potentially be targeted to treat metabolic inflexibility and prevent cardiac maladaptation during POH. We test our new paradigm with three specific aims: 1) using transgenic mice, we will evaluate the effect of modifying O-GlcNAc levels on left ventricular function and remodeling in POH, 2) we will determine the effect of modifying O-GlcNAc levels on fatty acid oxidation, glucose oxidation and glycolysis during POH, 3) we will determine the regulation of HBP flux and O-GlcNAc levels during POH. Our project provides essential insights into the regulation of fuel sources during POH, along with determining the effects of increased O-GlcNAc levels during POH. This knowledge could help develop of new therapeutic approaches to prevent or treat the common clinical problem heart failure from POH. This project addresses key knowledge deficits on the regulation of HBP flux and protein O-GlcNAc during hypertrophy, as well as their functional effects during hypertrophy. They will, therefore, provide essential insights on targeting these mechanisms for preventing or treating heart failure.

项目概要 一系列疾病，从高血压到结构性心脏病，如主动脉瓣狭窄或缩窄 主动脉，导致心脏压力超负荷。作为回应，心脏会出现肥大（称为 压力超负荷肥大（POH），可促进适应或导致心力衰竭。理解 这些相反的临床结果背后的机制将创造新的治疗机会。这 无压力的心脏主要依靠脂肪酸作为燃料，但会根据可用性改变能源来源。波赫 导致心脏增加对葡萄糖获取能量的依赖，但不幸的是，这种代谢不灵活 影响肥厚生长和心室功能障碍。因此，改善用于资源的平衡 POH期间的燃料产生可以促进适应，但针对这种方法的治疗尚未得到证实 部分实现是因为这些代谢变化背后的机制尚不完全清楚。我们的 初步结果确定了一种可能影响底物对能量偏好的新机制 我们在本提案中追求的 POH 过程中柠檬酸循环的生产。翻译后修饰 O-连接 β-N-乙酰氨基葡萄糖 (O-GlcNAc) 在全球范围内增加人类肥大的心脏和 动物。一个广泛接受的教条假设己糖胺生物合成途径（HBP）导致 蛋白质的 O-GlcNAc 酰化取决于代谢变化，尤其是糖酵解通量。然而，我们最近 数据显示相反的情况； HBP 通量和 O-GlcNAc 水平决定心脏燃料利用率。我们最近 对 POH 期间蛋白质 O-GlcNAc 变化进行了最全面的评估，并初步 发现脂肪酸和葡萄糖代谢的多种酶的 O-GlcNAc 水平增加。因此， 我们提出了一个新的范例，即 HBP 通量和 O-GlcNAc 是柠檬酸燃料偏好的关键调节剂 POH 期间的酸循环。因此，O-GlcNAc 可能有潜力用于治疗代谢不灵活并预防 POH 期间心脏适应不良。我们测试我们的新范式有三个具体目标：1）使用转基因 小鼠，我们将评估改变 O-GlcNAc 水平对左心室功能和重构的影响 POH，2) 我们将确定改变 O-GlcNAc 水平对脂肪酸氧化、葡萄糖氧化的影响 和 POH 期间的糖酵解，3) 我们将确定 POH 期间 HBP 通量和 O-GlcNAc 水平的调节。 我们的项目提供了对 POH 期间燃料源监管的重要见解，并确定 POH 期间 O-GlcNAc 水平增加的影响。这些知识可以帮助开发新的治疗方法 预防或治疗 POH 常见临床问题心力衰竭的方法。该项目解决了关键 肥大过程中 HBP 通量和蛋白 O-GlcNAc 调节的知识缺陷及其作用 肥大期间的功能影响。因此，他们将提供针对这些目标的重要见解 预防或治疗心力衰竭的机制。