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.

动脉粥样硬化是一种进行性慢性血管壁炎症性疾病，在整个疾病发展过程中受到氧化应激的调节。内皮功能障碍是动脉粥样硬化发展的关键起始步骤，越来越多的证据表明线粒体活性氧 (ROS) 是一种炎症性疾病。内皮功能障碍和血管炎症的重要贡献者烟酰胺核苷酸转氢酶（NNT）正在成为调节线粒体 NADPH 水平的重要酶。通过调节线粒体氧化还原音（ROS 产生和去除的平衡）对许多代谢途径产生重大影响。我们的初步数据支持这一概念，并表明 C57Bl/6J (6J) 细胞中 NNT 的缺失导致了不同的线粒体。生物能量特征和以超氧化物产生增加和谷胱甘肽过氧化物酶活性降低为特征的促氧化线粒体表型表明，我们发现与高脂肪饮食相比，6J 动物更容易受到高脂肪饮食诱导的斑块形成。 C57Bl/6N (6N)。斑块形成是由两种动物的血浆脂质增加引起的，然而，用线粒体超氧化物歧化酶模拟物 MitoTEMPO 治疗对 6N 和 6J 动物的血清脂质和斑块形成产生了明显的影响。 6N 动物中的脂质，而不是 6J 中的脂质，令人惊讶的是，6J 动物中的斑块形成加剧，这表明线粒体活性氧在基于这些发现，我们提出 NNT 活性的丧失会导致促氧化线粒体表型，从而通过增强线粒体 ROS 产生、内皮功能障碍和血管炎症来恶化动脉粥样硬化的进展。假设，提出的研究将确定 i) NNT 是否抑制线粒体 ROS 产生并保留人血管内皮细胞中的正常内皮•NO 功能 ii) 是否减少； NNT 表达将增加线粒体 ROS 的产生并刺激 Nox 活性，从而导致内皮功能障碍；以及 iii）如果内皮 NNT 严格调节高脂肪饮食治疗小鼠的线粒体氧化还原张力和血管功能，则拟议研究的数据将确定 NNT 是主要因素。线粒体功能和 ROS 产生的调节因子，其缺失会促进内皮功能障碍和血管炎症，从而加剧动脉粥样硬化的发展，导致斑块形成增加。