Publications by authors named "Melanie Vogler"

5 Publications

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Hypoxia suppresses myofibroblast differentiation by changing RhoA activity.

J Cell Sci 2019 02 18;132(5). Epub 2019 Feb 18.

Institute of Cardiovascular Physiology, University Medical Center, Georg-August University Göttingen, 37073 Göttingen, Germany

Fibroblasts show a high range of phenotypic plasticity, including transdifferentiation into myofibroblasts. Myofibroblasts are responsible for generation of the contraction forces that are important for wound healing and scar formation. Overactive myofibroblasts, by contrast, are involved in abnormal scarring. Cell stretching and extracellular signals such as transforming growth factor β can induce the myofibroblastic program, whereas microenvironmental conditions such as reduced tissue oxygenation have an inhibitory effect. We investigated the effects of hypoxia on myofibroblastic properties and linked this to RhoA activity. Hypoxia reversed the myofibroblastic phenotype of primary fibroblasts. This was accompanied by decreased αSMA (ACTA2) expression, alterations in cell contractility, actin reorganization and RhoA activity. We identified a hypoxia-inducible induction of ARHGAP29, which is critically involved in myocardin-related transcription factor-A (MRTF-A) signaling, the differentiation state of myofibroblasts and modulates RhoA activity. This novel link between hypoxia and MRTF-A signaling is likely to be important for ischemia-induced tissue remodeling and the fibrotic response.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/jcs.223230DOI Listing
February 2019

Oxygen-dependent regulation of aquaporin-3 expression.

Hypoxia (Auckl) 2016 21;4:91-97. Epub 2016 Apr 21.

Institute of Cardiovascular Physiology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany.

The purpose of this study was to investigate whether aquaporin-3 (AQP3) expression is altered in hypoxia and whether hypoxia-inducible transcription factor (HIF)-1 regulates the hypoxic expression. AQP3 mRNA expression was studied in L929 fibrosarcoma cells and in several tissues derived from mice that were subjected to hypoxia. Computational analysis of the AQP3 promoter revealed conserved HIF binding sites within close proximity to the translational start site, and chromatin immunoprecipitation assays confirmed binding of HIF-1α to the endogenous hypoxia response elements. Furthermore, hypoxia resulted in increased expression of AQP3 mRNA in L929 fibrosarcoma cells. Consistently, shRNA-mediated knockdown of HIF-1α greatly reduced the hypoxic induction of AQP3. In addition, mRNA analysis of organs from mice exposed to inspiratory hypoxia demonstrated pronounced hypoxia-inducible expression of AQP3 in the kidney. Overall, our findings suggest that AQP3 expression can be regulated at the transcriptional level and that AQP3 represents a novel HIF-1 target gene.
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http://dx.doi.org/10.2147/HP.S97681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085303PMC
April 2016

Circulating Endothelial Cells Expressing the Angiogenic Transcription Factor Krüppel-Like Factor 4 are Decreased in Patients with Coronary Artery Disease.

Microcirculation 2015 Nov;22(8):700-10

Department of Cardiology and Pulmonary Medicine, University Medical Center Göttingen, Göttingen, Germany.

Objective: The zinc finger transcription factor KLF4 is known to control diverse EC functions.

Methods: The functional role of KLF4 for angiogenesis and its association with CAD was examined in HUVECs and human CECs.

Results: In two different angiogenesis assays, siRNA-mediated KLF4 downregulation impaired HUVEC sprouting and network formation. Conversely, KLF4 overexpression increased HUVEC sprouting and network formation. Similar findings were observed after incubation of HUVECs with CdM from KLF4 cDNA-transfected cells, suggesting a role of paracrine factors for mediating angiogenic KLF4 effects. In this regard, VEGF expression was increased in KLF4-overexpressing HUVECs, whereas its expression was reduced in HUVECs transfected with KLF4 siRNA. To examine the relevance of our in vitro findings for human endothelial dysfunction, we analyzed the expression of KLF4 in CECs of patients with stable CAD. Flow cytometry analyses revealed decreased numbers of KLF4-positive CECs in peripheral blood from CAD patients compared to healthy controls.

Conclusions: Our findings suggest that KLF4 may represent a potential biomarker for EC dysfunction. In the future, (therapeutic) modulation of KLF4 may be useful in regulating EC function during vascular disease processes.
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http://dx.doi.org/10.1111/micc.12226DOI Listing
November 2015

Pre- and post-conditional inhibition of prolyl-4-hydroxylase domain enzymes protects the heart from an ischemic insult.

Pflugers Arch 2015 Oct 13;467(10):2141-9. Epub 2015 Jan 13.

Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.

Several genetically modified mouse models implicated that prolyl-4-hydroxylase domain (PHD) enzymes are critical mediators for protecting tissues from an ischemic insult including myocardial infarction by affecting the stability and activation of hypoxia-inducible factor (HIF)-1 and HIF-2. Thus, the current efforts to develop small-molecule PHD inhibitors open a new therapeutic option for myocardial tissue protection during ischemia. Therefore, we aimed to investigate the applicability and efficacy of pharmacological HIFα stabilization by a small-molecule PHD inhibitor in the heart. We tested for protective effects in the acute phase of myocardial infarction after pre- or post-conditional application of the inhibitor. Application of the specific PHD inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) resulted in HIF-1α and HIF-2α accumulation in heart muscle cells in vitro and in vivo. The rapid and robust responsiveness of cardiac tissue towards ICA was further confirmed by induction of the known HIF target genes heme oxygenase-1 and PHD3. Pre- and post-conditional treatment of mice undergoing myocardial infarction resulted in a significantly smaller infarct size. Tissue protection from ischemia after pre- or post-conditional ICA treatment demonstrates that there is a therapeutic time window for the application of the PHD inhibitor (PHI) post-myocardial infarction, which might be exploited for acute medical interventions.
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http://dx.doi.org/10.1007/s00424-014-1667-zDOI Listing
October 2015

Hypoxia modulates fibroblastic architecture, adhesion and migration: a role for HIF-1α in cofilin regulation and cytoplasmic actin distribution.

PLoS One 2013 18;8(7):e69128. Epub 2013 Jul 18.

Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.

Cells can adapt to hypoxia by various mechanisms. Yet, hypoxia-induced effects on the cytoskeleton-based cell architecture and functions are largely unknown. Here we present a comprehensive analysis of the architecture and function of L929 fibroblasts under hypoxic conditions (1% O2). Cells cultivated in hypoxia showed striking morphological differences as compared to cells cultivated under normoxic conditions (20% O2). These changes include an enlargement of cell area and volume, increased numbers of focal contacts and loss of cell polarization. Furthermore the β- and γ-actin distribution is greatly altered. These hypoxic adjustments are associated with enhanced cell spreading and a decline of cell motility in wound closure and single cell motility assays. As the hypoxia-inducible factor-1α (HIF-1α) is stabilised in hypoxia and plays a pivotal role in the transcriptional response to changes in oxygen availability we used an shRNA-approach to examine the role of HIF-1α in cytoskeleton-related architecture and functions. We show that the observed increase in cell area, actin filament rearrangement, decrease of single cell migration in hypoxia and the maintenance of p-cofilin levels is dependent on HIF-1α stabilisation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069128PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715466PMC
February 2014