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

氧化应激在心力衰竭的病理生理学中起着因果作用。心肌细胞内活性氧(ROS)的重要来源是线粒体，也包括NADPH氧化酶(NOX2)。我们以前的工作发现了一个新的机制，即心脏后负荷增加如何增加线粒体ROS的释放。这一机制涉及电子传递链上NADH的氧化和烟酰胺核苷酸转氢酶(NNT)的反向氧化。相比之下，其他人的工作表明，NOX2的激活是对心脏前或后负荷升高的反应。本项目的目的是阐明前或后负荷增加对线粒体和依赖NOX2的ROS产生的影响，以及这两个来源之间存在的相互作用。为此，我们应用了显微镜技术(涉及单个心肌细胞的测力)和转基因技术(使用新颖和更特异的线粒体或胞浆中过氧化氢的报告)的独特组合。该项目将指导开发特定的治疗方法，以减少心脏氧化应激，这可能会改善心力衰竭患者的心功能。

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.