Stefanie Dimmeler

CardioVasculäres Centrum Frankfurt, Frankfurt, Hesse, Germany

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Publications (396)3634.98 Total impact

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    ABSTRACT: Cellular metabolism was recently shown to regulate endothelial cell phenotype profoundly. Whether the atheroprotective biomechanical stimulus elicited by laminar shear stress modulates endothelial cell metabolism is not known.
    Arteriosclerosis Thrombosis and Vascular Biology 10/2014; · 6.34 Impact Factor
  • Stefanie Dimmeler, Seppo Ylä-Herttuala
    Circulation Research 09/2014; 115(8):680-2. · 11.86 Impact Factor
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    ABSTRACT: Cell therapy of acute myocardial infarction (AMI) with bone marrow-derived mononuclear cells (BMC) resulted in a modest improvement of cardiac function, but clinical trial results were heterogeneous. After isolation, BMC are maintained in medium supplemented with complements such as autologous serum to maintain optimal cell viability until administration. In the REPAIR-AMI trial, serum was prepared using tubes containing coagulation accelerators, but the regulatory agency recommended using additive-free tubes for the pivotal BAMI trial. Here, we show that serum obtained from patients with anti-thrombotic therapy in tubes without coagulation accelerators induces clotting, thereby rendering the cell product unsuitable for intra-coronary application. Specifically, systemic treatment of patients with low doses of heparin prevented efficient coagulation ex vivo, and the resulting partially clotted plasma induced cell aggregation within 1-18 h in the cell product. Utmost care has to be taken to test autologous components of cell products before clinical use. The development of media including the appropriate recombinant growth factors for maintaining cell functionality ex vivo may be warranted.
    Journal of Cardiovascular Translational Research 09/2014; · 3.06 Impact Factor
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    Stefanie Dimmeler, Sheng Ding, Thomas A Rando, Alan Trounson
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    ABSTRACT: The scientific community is currently witnessing substantial strides in understanding stem cell biology in humans; however, major disappointments in translating this knowledge into medical therapies are flooding the field as well. Despite these setbacks, investigators are determined to better understand the caveats of regeneration, so that major pathways of repair and regrowth can be exploited in treating aged and diseased tissues. Last year, in an effort to contribute to this burgeoning field, Nature Medicine, in collaboration with the Volkswagen Foundation, organized a meeting with a panel of experts in regenerative medicine to identify the most pressing challenges, as well as the crucial strategies and stem cell concepts that can best help advance the translational regenerative field. Here some experts who participated in the meeting provide an outlook at some of those key issues and concepts.
    Nature medicine. 08/2014; 20(8):814-21.
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    ABSTRACT: Objective To assess the effect of long-term pharmacological inhibition of miR-21 in a model of metabolic syndrome and obesity.Design and Methods Aged db/db mice were treated with locked nucleic acid-modified anti-miRs directed against miR-21 (LNA-21), control LNAs or PBS for 18 weeks. Cardiac function was assessed by echocardiography and the effect on body weight and white adipose tissue (WAT) was evaluated.ResultsMiR-21 expression was efficiently inhibited in the heart and WAT with no apparent liver toxicity or deterioration of kidney function. MiR-21 inhibition had no effect on cardiac hypertrophy as well as systolic and diastolic cardiac functions. However, levels of cardiac collagen 1 were modestly reduced in LNA-21 treated mice. MiR-21 inhibition reduced body weight, as well as adipocyte size and serum triglycerides were significantly decreased. The miR-21 targets TGFβ-receptor 2 (TGFBR2) and phosphatase and tensin homolog (PTEN) were derepressed in WAT of LNA-21 treated mice and Sprouty1 and 2 were increased after miR-21 inhibition.Conclusions Long-term treatment with LNA-21 is safe and efficiently suppresses miR-21 expression. Cardiac function was not affected. LNA-21 treatment led to a significant weight loss and reduces adipocyte size as well as derepression of the targets TGFRB2, PTEN, and Sprouty1 and 2.
    Obesity 08/2014; · 3.92 Impact Factor
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    ABSTRACT: MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific LNA-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice.
    Cardiovascular research. 06/2014;
  • Reinier A Boon, Stefanie Dimmeler
    Arteriosclerosis Thrombosis and Vascular Biology 05/2014; · 6.34 Impact Factor
  • Yosif Manavski, Reinier A Boon, Stefanie Dimmeler
    Circulation Research 03/2014; 114(7):1077-9. · 11.86 Impact Factor
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    ABSTRACT: The human genome harbors a large number of sequences encoding for RNAs that are not translated but control cellular functions by distinct mechanisms. The expression and function of the longer transcripts namely the long non-coding RNAs (lncRNAs) in the vasculature is largely unknown. Here, we characterized the expression of lncRNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1; also known as MALAT-1 or NEAT2). Endothelial cells of different origin express high levels of the conserved lncRNAs MALAT1, TUG1, MEG3, linc00657 and linc00493. MALAT1 was significantly increased by hypoxia and controls a phenotypic switch in endothelial cells. Silencing of MALAT1 by siRNAs or GapmeRs induced a pro-migratory response and increased basal sprouting and migration, whereas proliferation of endothelial cells was inhibited. When angiogenesis was further stimulated by VEGF, MALAT1 siRNAs induced discontinuous sprouts indicative of defective proliferation of stalk cells. In vivo studies confirmed that genetic ablation of MALAT1 inhibited proliferation of endothelial cells and reduced neonatal retina vascularization. Pharmacological inhibition of MALAT1 by GapmeRs reduced blood flow recovery and capillary density after hind limb ischemia. Gene expression profiling followed by confirmatory qRT-PCR demonstrated that silencing of MALAT1 impaired the expression of various cell cycle regulators. Silencing of MALAT1 tips the balance from a proliferative to a migratory endothelial cell phenotype in vitro and its genetic deletion or pharmacological inhibition reduces vascular growth in vivo.
    Circulation Research 03/2014; · 11.86 Impact Factor
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    ABSTRACT: β1-Integrins are essential for angiogenesis. The mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis remain elusive. Brag2 is a guanine nucleotide exchange factor for the small Arf-GTPases Arf5 and Arf6. The role of Brag2 in EC and angiogenesis and the underlying molecular mechanisms remain unclear. siRNA-mediated Brag2-silencing reduced EC angiogenic sprouting and migration. Brag2-siRNA transfection differentially affected α5β1- and αVβ3-integrin function: specifically, Brag2-silencing increased focal/fibrillar adhesions and adhesion on β1-integrin ligands (fibronectin and collagen), while reducing the adhesion on the αVβ3-integrin ligand, vitronectin. Consistent with these results, Brag2-silencing enhanced surface expression of α5β1-integrin, while reducing surface expression of αVβ3-integrin. Mechanistically, Brag2-mediated αVβ3-integrin-recycling and β1-integrin endocytosis and specifically of the active/matrix-bound α5β1-integrin present in fibrillar/focal adhesions (FA), suggesting that Brag2 contributes to the disassembly of FA via β1-integrin endocytosis. Arf5 and Arf6 are promoting downstream of Brag2 angiogenic sprouting, β1-integrin endocytosis and the regulation of FA. In vivo silencing of the Brag2-orthologues in zebrafish embryos using morpholinos perturbed vascular development. Furthermore, in vivo intravitreal injection of plasmids containing Brag2-shRNA reduced pathological ischemia-induced retinal and choroidal neovascularization. These data reveal that Brag2 is essential for developmental and pathological angiogenesis by promoting EC sprouting through regulation of adhesion by mediating β1-integrin internalization and link for the first time the process of β1-integrin endocytosis with angiogenesis.
    Archiv für Kreislaufforschung 03/2014; 109(2):404. · 7.35 Impact Factor
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    ABSTRACT: This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycaemic (ND-CMSC) and Type-2 diabetes patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as a potential pharmacological intervention to restore cellular function. D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 Serine 10 (H3S10P), decreased differentiation potential and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 Lysine 9 and Lysine 14 (H3K9Ac; H3K14Ac) was decreased while the trimethylation of histone H3 Lysine 9 and Lysine 27 (H3K9Me3; H3K27Me3) significantly increased. These observations were paralleled by a down-regulation of the GCN5-Related N-acetyltransferases (GNAT) p300/CBP associated factor (PCAF) and its isoform 5-alpha General Control of Amino Acid Synthesis (GCN5a), determining a relative decrease in total HAT activity. DNA CpG island hyper methylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT pro-activator SPV106, restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hyper methylation and recovered D-CMSC proliferation and differentiation. These results suggest that epigenetic interventions may reverse alterations in human cardiac mesenchymal cells obtained from diabetic patients.
    Diabetes 01/2014; · 7.90 Impact Factor
  • Konstantinos Stellos, Stefanie Dimmeler
    Circulation Research 01/2014; 114(1):3-4. · 11.86 Impact Factor
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    ABSTRACT: Disruption of the renal endothelial integrity is pivotal for the development of a vascular leak, tissue edema and consequently acute kidney injury. Kidney ischemia amplifies endothelial activation and up-regulation of pro-inflammatory mechanisms. After restoring a sufficient blood flow, the kidney is damaged through complex pathomechanisms that are classically referred to as ischemia and reperfusion injury, where the disruption of the inter-endothelial connections seems to be a crucial step in this pathomechanism. Focusing on the molecular cell-cell interaction, the fibrinopeptide Bβ15-42 prevents vascular leakage by stabilizing these inter-endothelial junctions. The peptide associates with vascular endothelial-cadherin, thus preventing early kidney dysfunction by preserving blood perfusion efficacy, edema formation and thus organ dysfunction. We intended to demonstrate the early therapeutic benefit of intravenously administered Bβ15-42 in a mouse model of renal ischemia and reperfusion. After 30 minutes of ischemia, the fibrinopeptide Bβ15-42 was administered intravenously before reperfusion was commenced for 1 and 3 hours. We show that Bβ15-42 alleviates early functional and morphological kidney damage as soon as 1 h and 3 h after ischemia and reperfusion. Mice treated with Bβ15-42 displayed a significantly reduced loss of VE-cadherin, indicating a conserved endothelial barrier leading to less neutrophil infiltration which in turn resulted in significantly reduced structural renal damage. The significant reduction in tissue and serum neutrophil gelatinase-associated lipocalin levels reinforced our findings. Moreover, renal perfusion analysis by color duplex sonography revealed that Bβ15-42 treatment preserved resistive indices and even improved blood velocity. Our data demonstrate the efficacy of early therapeutic intervention using the fibrinopeptide Bβ15-42 in the treatment of acute kidney injury resulting from ischemia and reperfusion. In this context Bβ15-42 may act as a potent renoprotective agent by preserving the endothelial and vascular integrity.
    PLoS ONE 01/2014; 9(1):e84432. · 3.53 Impact Factor
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    Stefanie Dimmeler, Céline Carret, Roberto Buccione
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    ABSTRACT: The new EMBO Press publishing platform reinforces the standing of EMBO Molecular Medicine as the journal that matches high quality and novel research with rigorous editorial and ethical standards, and cements the journal's global reach and relevance.
    EMBO Molecular Medicine 01/2014; 6(1):1. · 7.80 Impact Factor
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    ABSTRACT: Acute kidney injury (AKI) is one of the most important complications in hospitalized patients and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of AKI following ischemia and reperfusion (IR). Male adult C57Bl6 wild-type (wt) mice and TLR-3 knock-out (-/-) mice were subjected to 30 minutes bilateral selective clamping of the renal artery followed by reperfusion for 30 min 2.5h and 23.5 hours or subjected to sham procedures. TLR-3 down-stream signaling was activated already within 3 h of ischemia and reperfusion in post-ischemic kidneys of wt mice lead to impaired blood perfusion followed by a strong pro-inflammatory response with significant neutrophil invasion. In contrast, this effect was absent in TLR-3-/- mice. Moreover, the quick TLR-3 activation resulted in kidney damage that was histomorphologically associated with significantly increased apoptosis and necrosis rates in renal tubules of wt mice. This finding was confirmed by increased kidney injury marker NGAL in wt mice and a better preserved renal perfusion after IR in TLR-3-/- mice than wt mice. Overall, the absence of TLR-3 is associated with lower cumulative kidney damage and maintained renal blood perfusion within the first 24 hours of reperfusion. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of early acute kidney injury.
    PLoS ONE 01/2014; 9(4):e94366. · 3.53 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs, miRs) emerged as key regulators of gene expression. Germline hemizygous deletion of the gene that encodes the miR-17∼92 miRNA cluster was associated with microcephaly, short stature and digital abnormalities in humans. Mice deficient for the miR-17∼92 cluster phenocopy several features such as growth and skeletal development defects and exhibit impaired B cell development. However, the individual contribution of miR-17∼92 cluster members to this phenotype is unknown. Here we show that germline deletion of miR-92a in mice is not affecting heart development and does not reduce circulating or bone marrow-derived hematopoietic cells, but induces skeletal defects. MiR-92a-/- mice are born at a reduced Mendelian ratio, but surviving mice are viable and fertile. However, body weight of miR-92a-/- mice was reduced during embryonic and postnatal development and adulthood. A significantly reduced body and skull length was observed in miR-92a-/- mice compared to wild type littermates. µCT analysis revealed that the length of the 5th mesophalanx to 5th metacarpal bone of the forelimbs was significantly reduced, but bones of the hindlimbs were not altered. Bone density was not affected. These findings demonstrate that deletion of miR-92a is sufficient to induce a developmental skeletal defect.
    PLoS ONE 01/2014; 9(6):e101153. · 3.53 Impact Factor
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    ABSTRACT: The inhibition of microRNAs (miRs) in a spatiotemporally defined manner by an exogenous trigger would help to specifically target the biological activity and avoid off-target effects. Novel antimiRs directed against miR-92a can be activated by irradiation (see scheme; 3'-UTR=3'-untranslated region) In this way miR-92a is inhibited, the miR-92a target integrin α5 is derepressed, and angiogenesis of endothelial cells is enhanced.
    Angewandte Chemie International Edition 10/2013; · 11.34 Impact Factor
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    ABSTRACT: Although aberrant reactivation of embryonic gene programs is intricately linked to pathological heart disease, the transcription factors driving these gene programs remain ill-defined. Here we report that increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium. In line, mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy. Conversely, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. Furthermore, in vivo inhibition of miR-25 by a specific antagomir evoked spontaneous cardiac dysfunction and sensitized the murine myocardium to heart failure in a Hand2-dependent manner. Our results reveal that signalling cascades integrate with microRNAs to induce the expression of the bHLH transcription factor Hand2 in the postnatal mammalian myocardium with impact on embryonic gene programs in heart failure.
    Nature Cell Biology 10/2013; · 20.76 Impact Factor
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    ABSTRACT: Four decades ago, angiogenesis was recognized as a therapeutic target for blocking cancer growth. Because of its importance, VEGF has been at the center stage of antiangiogenic therapy. Now, several years after FDA approval of an anti-VEGF antibody as the first antiangiogenic agent, many patients with cancer and ocular neovascularization have benefited from VEGF-targeted therapy; however, this anticancer strategy is challenged by insufficient efficacy, intrinsic refractoriness, and resistance. Here, we examine recent discoveries of new mechanisms underlying angiogenesis, discuss successes and challenges of current antiangiogenic therapy, and highlight emerging antiangiogenic paradigms.
    The Journal of clinical investigation 08/2013; 123(8):3190-200. · 15.39 Impact Factor

Publication Stats

34k Citations
3,634.98 Total Impact Points

Institutions

  • 2010–2014
    • CardioVasculäres Centrum Frankfurt
      Frankfurt, Hesse, Germany
  • 1997–2014
    • Goethe-Universität Frankfurt am Main
      • • Zentrum für Molekulare Medizin
      • • Zentrum der Inneren Medizin
      Frankfurt, Hesse, Germany
    • University of Wuerzburg
      • Department of Internal Medicine II
      Würzburg, Bavaria, Germany
  • 2013
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 2009–2013
    • University of Padova
      • • Department of Cardiac, Thoracic and Vascular Sciences
      • • Department of Medicine DIMED
      Padova, Veneto, Italy
    • Heinrich-Heine-Universität Düsseldorf
      • Institute of Molecular Mycology
      Düsseldorf, North Rhine-Westphalia, Germany
    • Max Planck Institute for Heart and Lung Research
      • Department IV Lung Development and Remodelling
      Stadt Bad Nauheim, Hesse, Germany
    • Newcastle University
      Newcastle-on-Tyne, England, United Kingdom
  • 1997–2013
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 2012
    • Universitätsklinikum Gießen und Marburg
      Marburg, Hesse, Germany
  • 2008–2012
    • Justus-Liebig-Universität Gießen
      • Department of Anaesthesiology and Intensive Care Medicine
      Gieben, Hesse, Germany
    • University of California, San Diego
      • Division of Cardiology
      San Diego, CA, United States
    • National Heart, Lung, and Blood Institute
      Maryland, United States
    • University of Cincinnati
      Cincinnati, Ohio, United States
  • 2011
    • VU University Medical Center
      • Department of Molecular Cell Biology and Immunology
      Amsterdam, North Holland, Netherlands
  • 2006
    • Technische Universität München
      • Nuklearmedizinische Klinik und Poliklinik
      München, Bavaria, Germany
  • 2004
    • Alliance for the Prudent Use of Antibiotics
      United States
  • 2001
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1993–1999
    • University of Cologne
      • Center for Experimental Medicine
      Köln, North Rhine-Westphalia, Germany
  • 1991–1993
    • Universität Konstanz
      Constance, Baden-Württemberg, Germany