Hexosamine biosynthesis pathway metabolism during cardiac hypertrophy

项目总结 范围广泛的疾病，从高血压到结构性心脏病，如主动脉瓣狭窄或狭窄 大动脉，对心脏造成压力超负荷的压力。作为回应，心脏经历肥大(称为 压力超负荷肥厚或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。这个 没有压力的心脏主要依靠脂肪酸作为燃料，但会根据可获得性改变能量来源。PoH 导致心脏增加对葡萄糖能量的依赖，但不幸的是，这种新陈代谢的不灵活性 影响肥大生长和心功能不全。因此，改善用于以下领域的资源平衡 POH期间产生的燃料可以促进适应，但针对这种方法的治疗尚未得到 部分是因为这些新陈代谢变化背后的机制还不完全清楚。我们的 初步结果确定了一种可能影响底物能量偏好的新机制 在POH期间的柠檬酸循环中的生产，我们在这项提案中追求。翻译后修饰语 通过O-连锁β-N-乙酰氨基葡萄糖(O-GlcNAc)在人类肥厚心脏和 动物。一种被广泛接受的教条认为，氨基己糖生物合成途径(HBP)导致 蛋白质的O-GlcN酰化依赖于代谢变化，尤其是糖酵解通量。然而，我们最近 数据显示恰恰相反；HBP流量和O-GlcNAc水平决定了心脏燃料的利用。我们最近 对POH期间蛋白质O-GlcNAc的变化进行了最全面的评估，并初步 在脂肪酸和葡萄糖代谢的多种酶上发现O-GlcNAc水平增加。因此， 我们提出了一个新的范式，即HBP通量和O-GlcNAc是柠檬酸燃料偏好的关键调节因素 POH过程中的酸循环。因此，O-GlcNAc有可能被用于治疗代谢不灵活和预防 POH期间心脏适应不良。我们测试我们的新范例有三个特定的目标：1)使用转基因 ，我们将评估改变O-GlcNAc水平对左心功能和重塑的影响。 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 3)POH过程中HBP流量和O-GlcNAc水平的调节。 我们的项目提供了对POH期间燃料来源监管的基本见解，以及确定 POH期间O-GlcNAc水平升高的影响。这一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。这个项目解决了关键问题 肥厚过程中HBP流量和蛋白O-GlcNAc调节的知识缺陷及其机制 肥大时的功能效应。因此，他们将提供针对这些目标的基本见解 预防或治疗心力衰竭的机制。

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.