Roles of NAD+ metabolism in diabetic cardiomyopathy

糖尿病是心力衰竭的主要危险因素之一，其特征在于代谢控制的丧失。心脏 失败是糖尿病患者死亡的主要原因。文献和初步研究支持NAD+氧化还原 不平衡促进糖尿病性心肌病。然而，改变NAD+代谢的机制 糖尿病心肌病的病因还远未确定。这个项目旨在剖析糖尿病压力如何 改变NAD+代谢，进而促进心脏功能障碍。我们的初步研究表明， NMRK可能是糖尿病患者NAD+代谢改变的致病机制 心中在目标1中，我们将使用参与NAD+代谢的代谢物和转录物的靶向分析， 确定NMRK上调如何调节心肌细胞中的NAD+代谢。康贝特人将以 NMRK上调在糖尿病心肌病进展中的病理意义 相关病毒介导的糖尿病小鼠中的过度表达。我们的试验数据表明钙调素的乙酰化- 依赖性蛋白激酶II（CaMKII），一种调节心脏功能的关键激酶，可能有助于糖尿病 心肌病在目标2中，我们将过表达乙酰化突变体，并测试乙酰化突变体的乙酰化 CaMKII在体外调节心肌细胞和线粒体功能，在体内调节糖尿病心肌病。这 该项目将探索NAD+代谢调节糖尿病心肌病的新模式。很长的- 长期目标是确定新的治疗靶点，以治疗糖尿病引起的心功能障碍，特别是 舒张功能障碍是一种日益流行的疾病，没有特定的治疗方案。

Diabetes is one of the major risk factors of heart failure and is characterized by a loss of metabolic control. Heart failure is the main cause of death for diabetic patients. Literature and pilot studies support that NAD+ redox imbalance promotes diabetic cardiomyopathy. However, mechanisms by which altered NAD+ metabolism contributes to diabetic cardiomyopathy are far from established. This project aims to dissect how diabetic stress alters NAD+ metabolism, and in turn promotes cardiac dysfunction. Our pilot studies show that up-regulated nicotinamide riboside kinase (NMRK) could be a pathogenic mechanism of altered NAD+ metabolism in diabetic hearts. In Aim 1, we will use targeted analyses of metabolites and transcripts involved in NAD+ metabolism to determine how NMRK up-regulation regulates NAD+ metabolism in cardiomyocytes. We will determine the pathogenic significance of NMRK up-regulation to the progression of diabetic cardiomyopathy using adeno- associated virus-mediated over-expression in diabetic mice. Our pilot data identify that acetylation of calmodulin- dependent protein kinase II (CaMKII), a key kinase regulating heart function, may contribute to diabetic cardiomyopathy. In Aim 2, we will over-express acetylation mutants, and test the hypothesis that acetylation of CaMKII regulates cardiomyocyte and mitochondrial function in vitro, and diabetic cardiomyopathy in vivo. This project will explore an emerging paradigm that NAD+ metabolism regulates diabetic cardiomyopathy. The long- term goal is to identify new therapeutic targets to treat cardiac dysfunction induced by diabetes, especially for diastolic dysfunction that is a growing epidemic, and has no specific treatment regimen.