Stefanie Dimmeler

Goethe-Universität Frankfurt am Main, Frankfurt, Hesse, Germany

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Publications (419)3859.81 Total impact

  • Source
    Circulation Research 04/2015; DOI:10.1161/RES.0000000000000054 · 11.09 Impact Factor
  • Birgit Assmus, Stefanie Dimmeler, Andreas M Zeiher
    Circulation Research 04/2015; 116(8):1291-2. DOI:10.1161/CIRCRESAHA.115.306330 · 11.09 Impact Factor
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    ABSTRACT: The contribution of myeloid cells to tumor microenvironments is a decisive factor in cancer progression. Tumor associated macrophages (TAMs) mediate tumor invasion and angiogenesis through matrix re-modeling, immune modulation and release of pro-angiogenic cytokines. Nothing is known about how pathogenic bacteria affect myeloid cells in these processes. Here we show that Bartonella henselae, a bacterial pathogen causing vasculoproliferative diseases (bacillary angiomatosis) reprograms human Myeloid Angiogenic Cells (MACs), a pro-angiogenic subset of circulating progenitor cells, towards a TAM-like phenotype with increased pro-angiogenic capacity. B. henselae infection resulted in inhibition of cell death, activation of angiogenic cellular programs and induction of M2 macrophage polarization. MACs infected with B. henselae incorporated into endothelial sprouts and increased angiogenic growth. Infected MACs developed a vascular mimicry phenotype in vitro and expression of B. henselae adhesin A (BadA) was essential in inducing these angiogenic effects. Secretome analysis revealed that increased pro-angiogenic activities were associated with the creation of a tumor-like microenvironment dominated by angiogenic-inflammatory cytokines and matrix re-modeling compounds. Our results demonstrate that manipulation of myeloid cells by pathogenic bacteria can contribute to microenvironmental regulation of pathological tissue growth and suggest parallels underlying both bacterial infections and cancer. This article is protected by copyright. All rights reserved.
    Cellular Microbiology 04/2015; DOI:10.1111/cmi.12447 · 4.82 Impact Factor
  • Shizuka Uchida, Stefanie Dimmeler
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    ABSTRACT: The mechanisms by which exercise regulates physiological cardiac growth and protects against maladaptive remodeling of the heart have been long sought after. In this issue, Liu et al. (2015) report that microRNAs are important regulators of exercise responses in the heart. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 04/2015; 21(4). DOI:10.1016/j.cmet.2015.03.014 · 16.75 Impact Factor
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    ABSTRACT: microRNAs (miRs) regulate vascular diseases such as atherosclerosis and cancer. miR-126 is important for endothelial cell signaling and promotes angiogenesis, protects against atherosclerosis, and reduces breast cancer cell growth and metastasis. The overexpression of miR-126, therefore, may be an attractive therapeutic strategy for the treatment of cardiovascular disease or cancer. Here we report a novel strategy to deliver miR-126 to endothelial and breast cancer cells. We tested three different strategies to deliver miR-126 by linking the miR to an aptamer for the ubiquitously expressed transferrin receptor (transferrin receptor aptamer, TRA). Linking the precursor of miR-126 (pre-miR-126) to the TRA by annealing of a complementary stick led to efficient uptake and processing of miR-126, resulting in the delivery of 1.6×10(6)±0.3×10(6) copies miR-126-3p per ng RNA in human endothelial cells and 7.4×10(5)±2×10(5) copies miR-126-3p per ng in MCF7 breast cancer cells. The functionality of the active TRA-miR-126 chimera was further demonstrated by showing that the chimera represses the known miR-126 target VCAM-1 and improved endothelial cell sprouting in a spheroid assay. Moreover, the TRA-miR-126 chimera reduced proliferation and paracrine endothelial cell recruitment of breast cancer cells to a similar extent as miR-126-3p mimics introduced by conventional liposome-based transfection. Together, this data demonstrates that pre-miR-126 can be delivered by a non-specific aptamer to exert biological functions in two different cell models. The use of the TRA-miR-126 chimera or the combination of the delivery strategy with other endothelial or tumor specific aptamers may provide an interesting therapeutic option to treat vascular disease or cancers.
    04/2015; DOI:10.1089/nat.2014.0501
  • Nicolas Jaé, Stefanie Dimmeler
    Circulation Research 03/2015; 116(7):1104-1106. DOI:10.1161/CIRCRESAHA.115.306051 · 11.09 Impact Factor
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    ABSTRACT: The amyloid beta peptide is the major protein constituent of neuritic plaques in Alzheimer disease and appears to play a central role in vascular inflammation pathophysiology. This study sought to determine the clinical value of amyloid-beta 1-40 (Abeta40) measurement in predicting cardiovascular (CV) mortality in patients with coronary heart disease (CHD) and arterial stiffness progression in young healthy subjects. Abeta40 was retrospectively measured in blood samples collected from 3 independent prospective cohorts and 2 case-control cohorts (total N = 1,464). Major adverse cardiac events (MACE) were assessed in the 2 prospective cohorts (n = 877) followed for a median of 4.4 years. To look at effects on subclinical disease, arterial stiffness was evaluated at baseline and after 5-year follow-up (n = 107) in young healthy subjects. The primary endpoint was the predictive value of Abeta40 for CV mortality and outcomes in patients with CHD. In Cox proportional hazards models adjusted for age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, high-sensitivity C-reactive protein, and high-sensitivity troponin T, Abeta40 independently predicted CV death and MACE in patients with CHD (p < 0.05 for all). After multivariate adjustment, Abeta40 levels conferred a substantial enhancement of net reclassification index and integrated discrimination improvement of individuals at risk in the total combined CHD cohort over the best predictive model. Further cohort-based analysis revealed that Abeta40 levels were significantly and independently associated with arterial stiffness progression, incident subclinical atherosclerosis, and incident CHD. Measuring blood levels of Abeta40 identified patients at high risk for CV death. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
    Journal of the American College of Cardiology 03/2015; 65(9):904-16. DOI:10.1016/j.jacc.2014.12.035 · 15.34 Impact Factor
  • Shizuka Uchida, Stefanie Dimmeler
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    ABSTRACT: In recent year, increasing evidence suggests that noncoding RNAs play important roles in the regulation of tissue homeostasis and pathophysiological conditions. Besides small noncoding RNAs (eg, microRNAs), >200-nucleotide long transcripts, namely long noncoding RNAs (lncRNAs), can interfere with gene expressions and signaling pathways at various stages. In the cardiovascular system, studies have detected and characterized the expression of lncRNAs under normal physiological condition and in disease states. Several lncRNAs are regulated during acute myocardial infarction (eg, Novlnc6) and heart failure (eg, Mhrt), whereas others control hypertrophy, mitochondrial function and apoptosis of cardiomyocytes. In the vascular system, the endothelial-expressed lncRNAs (eg, MALAT1 and Tie-1-AS) can regulate vessel growth and function, whereas the smooth-muscle-expressed lncRNA smooth muscle and endothelial cell-enriched migration/differentiation-associated long noncoding RNA was recently shown to control the contractile phenotype of smooth muscle cells. This review article summarizes the data on lncRNA expressions in mouse and human and highlights identified cardiovascular lncRNAs that might play a role in cardiovascular diseases. Although our understanding of lncRNAs is still in its infancy, these examples may provide helpful insights how lncRNAs interfere with cardiovascular diseases. © 2015 American Heart Association, Inc.
    Circulation Research 02/2015; 116(4):737-750. DOI:10.1161/CIRCRESAHA.116.302521 · 11.09 Impact Factor
  • Reinier A Boon, Stefanie Dimmeler
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    ABSTRACT: MicroRNAs (miRNAs) are small noncoding RNAs that block translation or induce degradation of mRNA and thereby control patterns of gene expression. Acute myocardial infarction is a common cardiovascular event that results in cardiac remodelling and can consequently lead to the development of chronic heart failure. Several miRNAs have been shown to control important processes that contribute to the pathophysiological consequences of acute myocardial infarction. miRNAs can either promote or inhibit cardiomyocyte cell death, and also regulate postischaemic neovascularization. Cardiac regeneration can also be regulated by miRNAs that control cardiomyocyte proliferation or interfere with cardioprotective effects mediated by stem or progenitor cells. miRNAs can also be used for direct reprogramming of cardiac fibroblasts into cardiomyocytes. In this Review, we focus on the current understanding of the role of miRNAs in these processes, and particularly discuss the therapeutic potential of miRNAs in treating acute myocardial infarction.
    Nature Reviews Cardiology 12/2014; 12(3). DOI:10.1038/nrcardio.2014.207 · 10.15 Impact Factor
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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; DOI:10.1161/ATVBAHA.114.304277 · 5.53 Impact Factor
  • Stefanie Dimmeler, Seppo Ylä-Herttuala
    Circulation Research 09/2014; 115(8):680-2. DOI:10.1161/CIRCRESAHA.114.304973 · 11.09 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; 7(7). DOI:10.1007/s12265-014-9584-2 · 2.69 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. DOI:10.1038/nm.3627 · 28.05 Impact Factor
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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; 22(11). DOI:10.1002/oby.20852 · 4.39 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 06/2014; 9(6):e101153. DOI:10.1371/journal.pone.0101153 · 3.53 Impact Factor
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    ABSTRACT: Aims MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, 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 locked nucleic acid (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. Methods and results MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin alpha 5 and sirtuin1, and reduced eNOS expression in vitro. MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo, systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin a5 and sirtuin1. Conclusion Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.
    Cardiovascular Research 06/2014; 103(4). DOI:10.1093/cvr/cvu162 · 5.81 Impact Factor
  • Reinier A Boon, Stefanie Dimmeler
    Arteriosclerosis Thrombosis and Vascular Biology 05/2014; 34(7). DOI:10.1161/ATVBAHA.114.303572 · 5.53 Impact Factor
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    ABSTRACT: Background In the REPAIR-AMI trial, intracoronary infusion of bone marrow-derived cells (BMCs) was associated with a significantly greater recovery of contractile function in patients with acute myocardial infarction (AMI) at 4-month follow-up than placebo infusion. The current analysis investigates clinical outcome and predictors of event-free survival at 5 years. Methods and results In the multicentre, placebo-controlled, double-blind REPAIR-AMI trial, 204 patients received intracoronary infusion of BMCs (n = 101) or placebo (n = 103) into the infarct vessel 3-7 days following successful percutaneous coronary intervention. Fifteen patients died in the placebo group compared with seven patients in the BMC group (P = 0.08). Nine placebo-treated patients and five BMC-treated patients required rehospitalization for chronic heart failure (P = 0.23). The combined endpoint cardiac/cardiovascular/unknown death or rehospitalisation for heart failure was more frequent in the placebo compared with the BMC group (18 vs. 10 events; P = 0.10). Univariate predictors of adverse outcomes were age, the CADILLAC risk score, aldosterone antagonist and diuretic treatment, changes in left ventricular ejection fraction, left ventricular end-systolic volume, and N-terminal pro-Brain Natriuretic Peptide (all P < 0.01) at 4 months in the entire cohort and in the placebo group. In contrast, in the BMC group, only the basal (P = 0.02) and the stromal cell-derived factor-1-induced (P = 0.05) migratory capacity of the administered BMC were associated with improved clinical outcome. Conclusion In patients of the REPAIR-AMI trial, established clinical parameters are associated with adverse outcome at 5 years exclusively in the placebo group, whereas the migratory capacity of the administered BMC determines event-free survival in the BMC-treated patients. These data disclose a potency-effect relationship between cell therapy and long-term outcome in patients with AMI.
    European Heart Journal 05/2014; 35(19):1275-1283. DOI:10.1093/eurheartj/ehu062 · 14.72 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 04/2014; 9(4):e94366. DOI:10.1371/journal.pone.0094366 · 3.53 Impact Factor
  • Yosif Manavski, Reinier A Boon, Stefanie Dimmeler
    Circulation Research 03/2014; 114(7):1077-9. DOI:10.1161/CIRCRESAHA.114.303452 · 11.09 Impact Factor

Publication Stats

43k Citations
3,859.81 Total Impact Points

Institutions

  • 1997–2015
    • 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
  • 2013–2014
    • CardioVasculäres Centrum Frankfurt
      Frankfurt, Hesse, Germany
  • 1997–2012
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 2011
    • University of Padova
      Padua, Veneto, Italy
  • 2008
    • University of California, San Diego
      • Division of Cardiology
      San Diego, CA, United States
  • 2007
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
    • University of Florence
      Florens, Tuscany, Italy
    • Westchester Medical Center
      Valhalla, New York, United States
    • Novartis
      Bâle, Basel-City, Switzerland
  • 2005
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2004
    • University of Leicester
      Leiscester, England, United Kingdom
    • University of Hamburg
      Hamburg, Hamburg, Germany
    • Tufts University
      Бостон, Georgia, United States
  • 2003
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 1996–2003
    • University of Freiburg
      • Institute of Forensic Medicine
      Freiburg, Baden-Württemberg, Germany
    • University of Cologne
      • Center for Experimental Medicine
      Köln, North Rhine-Westphalia, Germany
  • 2002
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2001
    • University of Strasbourg
      Strasburg, Alsace, France
    • Evangelische Hochschule Freiburg, Germany
      Freiburg, Baden-Württemberg, Germany
  • 1991–1994
    • Universität Konstanz
      • Molecular Toxicology
      Constance, Baden-Württemberg, Germany