Nicotinamide nucleotide transhydrogenase regulates redox balance in atherosclerosis

烟酰胺核苷酸转氢酶调节动脉粥样硬化的氧化还原平衡

• 批准号: 10083960
• 负责人: DAVID M KRZYWANSKI
• 金额: $ 21.8万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10083960
• 关键词: Animals; Atherosclerosis; Bioenergetics; Biology; Blood Vessels; Cardiovascular Diseases; Cells; Data; Development; Disease; Endothelium; Enzymes; Equilibrium; Excision; High Fat Diet; Human; Lipids; Metabolic Pathway; Mitochondria; Mus; NAD(P)+ transhydrogenase; NADP; Oxidation-Reduction; Phenotype; Plasma; Production; Reactive Oxygen Species; Reduced Glutathione; Regulation; Role; Serum; Superoxide Dismutase; Superoxides; Testing; Vascular Endothelial Cell; chronic inflammatory disease; endothelial dysfunction; glutathione peroxidase; mimetics; oxidant stress; preservation; vascular inflammation

Atherosclerosis, a progressive chronic inflammatory disease of the vessel wall, is regulated by oxidant stress throughout the course of disease development. Endothelial dysfunction is a critical, initiating step in the development of atherosclerosis and increasing evidence implicates mitochondrial reactive oxygen species (ROS) as an important contributor to endothelial dysfunction and vascular inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is emerging as an important enzyme in the regulation of mitochondrial NADPH levels which can have a significant impact on a number of metabolic pathways through the regulation of mitochondrial redox tone (balance of ROS production and removal). Our preliminary data supports this concept and indicates that that the absence of NNT in C57Bl/6J (6J) cells led to distinct mitochondrial bioenergetic profiles and a pro-oxidative mitochondrial phenotype characterized by increased superoxide production and reduced glutathione peroxidase activity. Interestingly, we found that 6J animals are more susceptible to high fat diet induced plaque formation compared to C57Bl/6N (6N). Plaque formation was driven by increased plasma lipids in both animals. However, treatment with the mitochondria targeted superoxide dismutase mimetic MitoTEMPO had distinct effects on serum lipids and plaque formation in the 6N and 6J animals. MitoTEMPO treatment reduced plasma lipids in the 6N animals but not the 6J, and surprisingly, exacerbated plaque formation in the 6J animals, demonstrating a critical role for the production of mitochondrial reactive oxygen species in the development of atherosclerosis in these animals. Building upon these findings, we propose that the loss of NNT activity contributes to a pro-oxidative mitochondrial phenotype that exacerbates the progression of atheroscelrosis by enhancing mitochondrial ROS production, endothelial dysfunction, and vascular inflammation. To test this hypothesis, studies are proposed that will determine i) if NNT inhibits mitochondrial ROS production and preserves normal endothelial •NO function in human vascular endothelial cells; ii) if reduced NNT expression will increase mitochondrial ROS production and stimulate Nox activity that contributes to endothelial dysfunction; and iii) if endothelial NNT critically regulates mitochondrial redox tone and vascular function in mice treated with high fat diet. Data from the proposed studies will identify NNT as a master regulator of mitochondrial function and ROS production whose absence exacerbates the development of atherosclerosis by promoting endothelial dysfunction and vascular inflammation, leading to increased plaque development.

动脉粥样硬化是血管壁的进行性慢性炎症性疾病，在整个疾病发展过程中受氧化应激的调节。内皮功能障碍是动脉粥样硬化发展和越来越多的证据的重要一步，这意味着线粒体活性氧（ROS）是内皮功能障碍和血管感染的重要因素。烟酰胺核经氢化酶（NNT）正在作为调节线粒体NADPH水平的重要酶，通过调节线粒体卫生组织的调节（ROS产生和去除），可以对许多代谢途径产生重大影响。我们的初步数据支持了这一概念，并表明C57BL/6J（6J）细胞中NNT的缺失导致了明显的线粒体生物能谱和促氧化的线粒体表型，其特征是超级氧化物产生和谷胱甘肽多胆硫硫代酶活性的增加。有趣的是，我们发现与C57BL/6n（6n）相比，6J动物更容易受到高脂肪饮食诱导的斑块形成。两种动物的血浆脂质增加驱动了牙菌斑的形成。然而，用线粒体靶向超氧化物歧化酶模拟粒子po的治疗对6N和6J动物的血清脂质和斑块形成具有明显的影响。 Mitotempo治疗减少了6N动物中的血浆脂质，但并非6J，令人惊讶的是，在6J动物中加剧了斑块的形成，这表明在这些动物的动脉粥样硬化中产生线粒体反应性氧在产生线粒体反应性氧的作用至关重要。在这些发现的基础上，我们建议NNT活性的丧失有助于促氧化的线粒体表型，从而通过增强线粒体ROS产生，内皮功能障碍和血管感染来加剧动脉粥样硬化的进展。为了检验这一假设，提出了研究将确定将确定i）nNT抑制线粒体ROS的产生并保留正常内皮•在人血管内皮细胞中无功能的研究； ii）如果NNT表达降低将增加线粒体ROS的产生并刺激有助于内皮功能障碍的NOX活性； iii）如果内皮NNT严重调节了用高脂饮食治疗的小鼠中的线粒体氧化还原张力和血管功能。拟议研究的数据将确定NNT是线粒体功能和ROS产生的主要调节剂，其缺失通过促进内皮功能障碍和血管感染加剧了动脉粥样硬化的发展，从而导致斑块发育增加。