Impact of elevated pre- and afterload on production of reactive oxygen species in cardiac myocytes

前负荷和后负荷升高对心肌细胞活性氧产生的影响

• 批准号: 290177420
• 负责人: Professor Dr. Christoph Maack
• 金额: --
• 依托单位: Deutsches Krebsforschungszentrum (DKFZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290177420?language=en
• 关键词: Impact; elevated; pre; afterload; production

Oxidative stress plays a causal role in the pathophysiology of heart failure. Important sources of reactive oxygen species (ROS) in cardiac myocytes are mitochondria, but also NADPH oxidase (Nox2). Our previous work identified a novel mechanism how elevated cardiac afterload increases the emission of ROS from mitochondria. This mechanism involves the oxidation of NADH at the electron transport chain and the oxidation of NADPH via the reverse mode of the nicotinamide nucleotide transhydrogenase (Nnt). In contrast, the work of others suggested an activation of Nox2 in response to elevated cardiac pre- or afterload. The aim of the present project is to elucidate the consequences of elevated pre- or afterload on mitochondrial and Nox2-dependent ROS production as well as the interplay that exists between both sources. To this end, we apply a unique combination of microscopy technology (that involves force measurements on single cardiac myocytes) and transgenic technology (using novel and more specific reporters for hydrogen peroxide in mitochondria or the cytosol). The project will guide the development of specific treatments to reduce cardiac oxidative stress, which may improve cardiac function in patients with heart failure.

氧化应激在心力衰竭的病理生理学中起着因果作用。心肌细胞中活性氧（ROS）的重要来源是线粒体，但也是NADPH氧化酶（Nox 2）。我们以前的工作确定了一个新的机制，如何提高心脏后负荷增加释放的活性氧从线粒体。该机制涉及电子传递链上的NADH氧化和通过烟酰胺核苷酸转氢酶（Nnt）的反向模式氧化NADPH。相比之下，其他人的工作表明，Nox 2的激活是对心脏前负荷或后负荷升高的反应。本项目的目的是阐明升高的前负荷或后负荷对线粒体和Nox2依赖的ROS产生的影响，以及两种来源之间存在的相互作用。为此，我们应用显微镜技术（涉及单个心肌细胞的力测量）和转基因技术（使用线粒体或胞质中过氧化氢的新型和更特异性的报告）的独特组合。该项目将指导特定治疗方法的开发，以减少心脏氧化应激，这可能会改善心力衰竭患者的心脏功能。