Search

Reactive oxygen species (ROS) are not only toxic agents but also potent signaling molecules. NADPH oxidases are the sole enzymes to generate ROS playing an important role in redox signaling. They closely interact in several ways with hypoxia-inducible transcription factors of the HIF family. This signaling network is active under normoxic and hypoxic conditions as an important regulator of redox homeostasis. Members of the NADPH oxidases-HIF axis appear as interesting therapeutic targets for various disorders characterized by an impaired redox homeostasis. [ABSTRACT FROM AUTHOR]

SDF-1/CXCR4 activation facilitates myocardial repair. Therefore, we aimed to activate the HIF-1α target genes SDF-1 and CXCR4 by dimethyloxalylglycine (DMOG)-induced prolyl-hydroxylase (PH) inhibition to augment CXCR4+ cell recruitment and myocardial repair. SDF-1 and CXCR4 expression was analyzed under normoxia and ischemia ± DMOG utilizing SDF-1-EGFP and CXCR4-EGFP reporter mice. In bone marrow and heart, CXCR4-EGFP was predominantly expressed in CD45+/CD11b+ leukocytes which significantly increased after myocardial ischemia. PH inhibition with 500 μM DMOG induced upregulation of SDF-1 mRNA in human microvascular endothelial cells (HMEC-1) and aortic vascular smooth muscle cells (HAVSMC). CXCR4 was highly elevated in HMEC-1 but almost no detectable in HAVSMC. In vivo, systemic administration of the PH inhibitor DMOG without pretreatment upregulated nuclear HIF-1α and SDF-1 in the ischemic mouse heart associated with increased recruitment of CD45+/CXCR4-EGFP+/CD11b+ cell subsets. Enhanced PH inhibition significantly upregulated reparative M2 like CXCR4-EGFP+ CD11b+/CD206+ cells compared to inflammatory M2-like CXCR4-EGFP+ CD11b+/CD86+ cells associated with reduced apoptotic cell death, increased neovascularization, reduced scar size, and an improved heart function after MI. In summary, our data suggest increased PH inhibition as a promising tool for a customized upregulation of SDF-1 and CXCR4 expression to attract CXCR4+/CD11b+ cells to the ischemic heart associated with increased cardiac repair. Key messages: [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are among the leading causes of death worldwide. Reactive oxygen species (ROS) can act as damaging molecules but also represent central hubs in cellular signalling networks. Increasing evidence indicates that ROS play an important role in the pathogenesis of cardiovascular diseases, although the underlying mechanisms and consequences of pathophysiologically elevated ROS in the cardiovascular system are still not completely resolved. More recently, alterations of the epigenetic landscape, which can affect DNA methylation, post-translational histone modifications, ATP-dependent alterations to chromatin and non-coding RNA transcripts, have been considered to be of increasing importance in the pathogenesis of cardiovascular diseases. While it has long been accepted that epigenetic changes are imprinted during development or even inherited and are not changed after reaching the lineage-specific expression profile, it becomes more and more clear that epigenetic modifications are highly dynamic. Thus, they might provide an important link between the actions of ROS and cardiovascular diseases. This review will provide an overview of the role of ROS in modulating the epigenetic landscape in the context of the cardiovascular system.Linked Articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. [ABSTRACT FROM AUTHOR]

Arsenite (As(III)) is widely distributed in nature and can be found in water, food, and air. There is significant evidence that exposure to As(III) is associated with human cancers originated from liver, lung, skin, bladder, kidney, and prostate. Hypoxia plays a role in tumor growth and aggressiveness; adaptation to it is, at least to a large extent, mediated by hypoxia-inducible factor-1α (HIF-1α). In the current study, we investigated As(III) effects on HIF-1α under normoxia and hypoxia in the hepatoma cell line HepG2. We found that As(III) increased HIF-1α protein levels under normoxia while the hypoxia-mediated induction of HIF1α was reduced. Thereby, the As(III) effects on HIF-1α were dependent on both, transcriptional regulation via the transcription factor Nrf2 mediated by NOX4, PI3K/Akt, and ERK1/2 as well as by modulation of HIF-1α protein stability. In line, the different effects of As(III) via participation of HIF-1α and Nrf2 were also seen in tube formation assays with endothelial cells where knockdown of Nrf2 and HIF-1α abolished As(III) effects. Overall, the present study shows that As(III) is a potent inducer of HIF-1α under normoxia but not under hypoxia which may explain, in part, its carcinogenic as well as anti-carcinogenic actions. Key message: [ABSTRACT FROM AUTHOR]

Urotensin-II (U-II) has been considered as one of the most potent vasoactive peptides, although its physiological and pathophysiological role is still not finally resolved. Recent evidence suggests that it promotes angiogenic responses in endothelial cells, although the underlying signalling mechanisms are unclear. Reactive oxygen species derived from NADPH oxidases are major signalling molecules in the vasculature. Because NOX2 is functional in endothelial cells, we investigated the role of the NOX2-containing NADPH oxidase in U-II-induced angiogenesis and elucidated a possible contribution of hypoxia-inducible factor-1 (HIF-1), the master regulator of hypoxic angiogenesis, in the response to U-II. We found that U-II increases angiogenesis in vitro and in vivo, and these responses were prevented by antioxidants, NOX2 knockdown and in Nox2-/- mice. In addition, U-II-induced angiogenesis was dependent on HIF-1. Interestingly, U-II increased NOX2 transcription involving HIF-1, and chromatin immunoprecipitation confirmed NOX2 as a target gene of HIF-1. In support, NOX2 levels were greatly diminished in U-II-stimulated isolated vessels derived from mice deficient in endothelial HIF-1. Conversely, reactive oxygen species derived from NOX2 were required for U-II activation of HIF and upregulation of HIF-1. In line with this, U-II-induced upregulation of HIF-1 was absent in Nox2-/- vessels. Collectively, these findings identified HIF-1 and NOX2 as partners acting in concert to promote angiogenesis in response to U-II. Because U-II has been found to be elevated in cardiovascular disorders and in tumour tissues, this feed-forward mechanism could be an interesting anti-angiogenic therapeutic option in these disorders. [ABSTRACT FROM AUTHOR]

Unlabelled: A computer aided monitor-data processing system (CAMP-System) was developed in order to get a consistent and comprehensive database which can very precisely reflect intra-operative haemodynamic courses. The goal of the present study was to introduce a new method to scan and to gauge haemodynamic courses and to demonstrate its superiority over the traditional way of data processing based on a handwritten anaesthesia protocol.Methods: The computerized system was applied to a study which was designed to investigate the influence of ketanserin (K) vs. urapidil (U) on haemodynamic stability during cardiac operations. Twenty male patients scheduled for myocardial revascularization received either 20 mg K or 30 mg U. Heart rate, central venous, arterial and pulmonary artery pressures were measured and on-line recorded every 20 seconds by the computer record system. In the handwritten protocol these variables were registered at eight pre-defined time points. Computerized data processing (including artifact depletion and data condensation) was compared to the results evaluated from the handwritten protocol.Results: While the only significant differences in the handwritten protocol were slightly higher values of pulmonary artery pressures in group K, the computer analysis revealed a number of further differences. Higher maximum and a less stable time course of HR in group K in the pre-bypass phase and lower mean and standard deviation of MAP during cardiopulmonary bypass.Conclusion: Computerized data processing including automatic artifact suppression and data condensation was able to reveal differences in the course of haemodynamic variables that cannot be detected in a conventional handwritten protocol. [ABSTRACT FROM AUTHOR]

Exposure to chronic hypoxia results in pulmonary hypertension characterized by increased vascular resistance and pulmonary vascular remodeling, changes in functional parameters of the pulmonary vasculature, and right ventricular hypertrophy, which can eventually lead to right heart failure. The underlying mechanisms of hypoxia-induced pulmonary hypertension have still not been fully elucidated while no curative treatment is currently available. Commonly employed pre-clinical analytic methods are largely limited to invasive studies interfering with cardiac tissue or otherwise ex vivo functional studies and histopathology. In this work, we suggest volumetric optoacoustic tomography (VOT) for non-invasive assessment of heart function in response to chronic hypoxia. Mice exposed for 3 consecutive weeks to normoxia or chronic hypoxia were imaged in vivo with heart perfusion tracked by VOT using indocyanide green contrast agent at high temporal (100 Hz) and spatial (200 µm) resolutions in 3D. Unequivocal difference in the pulmonary transit time was revealed between the hypoxic and normoxic conditions concomitant with the presence of pulmonary vascular remodeling within hypoxic models. Furthermore, a beat-to-beat analysis of the volumetric image data enabled identifying and characterizing arrhythmic events in mice exposed to chronic hypoxia. The newly introduced non-invasive methodology for analysis of impaired pulmonary vasculature and heart function under chronic hypoxic exposure provides important inputs into development of early diagnosis and treatment strategies in pulmonary hypertension. [ABSTRACT FROM AUTHOR]