Roles of NAD+ metabolism in diabetic cardiomyopathy

糖尿病是心力衰竭的主要危险因素之一，其特征是代谢控制的丧失。心 失败是糖尿病患者死亡的主要原因。文献和试点研究支持NAD+氧化还原 不平衡会导致糖尿病心肌病。然而，改变NAD+代谢的机制 糖尿病心肌病的致病因素远未确定。该项目旨在剖析糖尿病应激是如何 改变NAD+代谢，进而促进心脏功能障碍。我们的试点研究表明，上调监管 烟酰胺核苷激酶(NMRK)可能是糖尿病NAD+代谢改变的致病机制之一 红心。在目标1中，我们将对参与NAD+代谢的代谢物和转录本进行有针对性的分析，以 确定NMRK上调如何调节心肌细胞中的NAD+代谢。我们将确定 腺病毒介导NMRK上调对糖尿病心肌病变进展的致病意义 糖尿病小鼠相关病毒介导的过度表达。我们的试验数据表明，钙调蛋白的乙酰化- 依赖性蛋白激酶II(CaMKII)是一种调节心脏功能的关键激酶，可能与糖尿病的发病有关 心肌病。在目标2中，我们将过度表达乙酰化突变体，并测试乙酰化 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 该项目将探索一种新兴的NAD+代谢调节糖尿病心肌病的范例。长的- 学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 舒张期功能障碍是一种日益流行的疾病，目前还没有特效的治疗方案。

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.