Stefanie Dimmeler

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

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Publications (431)3974.67 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Owing greatly to the advancement of next-generation sequencing (NGS), the amount of NGS data is increasing rapidly. Although there are many NGS applications, one of the most commonly used techniques 'RNA sequencing (RNA-seq)' is rapidly replacing microarray-based techniques in laboratories around the world. As more and more of such techniques are standardized, allowing technicians to perform these experiments with minimal hands-on time and reduced experimental/operator-dependent biases, the bottleneck of such techniques is clearly visible; that is, data analysis. Further complicating the matter, increasing evidence suggests most of the genome is transcribed into RNA; however, the majority of these RNAs are not translated into proteins. These RNAs that do not become proteins are called 'noncoding RNAs (ncRNAs)'. Although some time has passed since the discovery of ncRNAs, their annotations remain poor, making analysis of RNA-seq data challenging. Here, we examine the current limitations of RNA-seq analysis using case studies focused on the detection of novel transcripts and examination of their characteristics. Finally, we validate the presence of novel transcripts using biological experiments, showing novel transcripts can be accurately identified when a series of filters is applied. In conclusion, novel transcripts that are identified from RNA-seq must be examined carefully before proceeding to biological experiments. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
    Briefings in Bioinformatics 08/2015; DOI:10.1093/bib/bbv067 · 9.62 Impact Factor
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    ABSTRACT: This study aimed to determine whether the vascular endothelial growth factor (VEGF) family members soluble VEGF receptor 1 (also called soluble fms-like tyrosine kinase 1 (sFlt-1)) and placental growth factor (PlGF) could be used as biomarkers for pulmonary hypertension (PH).Consecutive patients undergoing right heart catheterisation were enrolled (those with mean pulmonary arterial pressure ≥25 mmHg were classed as having PH; those with mean pulmonary arterial pressure <25 mmHg acted as non-PH controls). Plasma from the time of PH diagnosis was analysed for PlGF and sFlt-1 using enzyme immunoassays.In total, 247 patients with PH were enrolled: 62 with idiopathic pulmonary arterial hypertension (IPAH), 14 with associated pulmonary arterial hypertension (APAH), 21 with collagen vascular disease (CVD), 26 with pulmonary venous hypertension, 67 with lung disease-associated PH and 57 with chronic thromboembolic PH. The non-PH control group consisted of 40 patients. sFlt-1 plasma levels were significantly higher in patients with IPAH, APAH, CVD and lung disease-associated PH versus controls; PlGF levels were significantly higher in all PH groups versus controls. The combination of sFlt-1 and PlGF resulted in a sensitivity of 83.7% with specificity of 100% for pulmonary arterial hypertension. There was no association between sFlt-1 or PlGF and haemodynamic parameters, 6-min walking distance or survival.In summary, PlGF and sFlt-1 are promising diagnostic biomarkers for PH. Copyright ©ERS 2015.
    European Respiratory Journal 08/2015; DOI:10.1183/13993003.00187-2015 · 7.13 Impact Factor
  • Tyler Weirick · David John · Stefanie Dimmeler · Shizuka Uchida
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    ABSTRACT: Increasing evidences suggest that most of the genome is transcribed into RNAs, but many of them are not translated into proteins. All those RNAs that do not become proteins are called "non-coding RNAs (ncRNAs)", which outnumbers protein-coding genes. Interestingly, these ncRNAs are shown to be more tissue specifically expressed than protein-coding genes. Given that tissue-specific expressions of transcripts suggest their importance in the expressed tissue, researchers are conducting biological experiments to elucidate the function of such ncRNAs. Owing greatly to the advancement of next generation techniques, especially RNA-seq, the amount of high-throughput data are increasing rapidly. However, due to the complexity of the data as well as its high volume, it is not easy to re-analyze such data to extract tissue-specific expressions of ncRNAs from published datasets. Here, we introduce a new knowledge database called "C-It-Loci", which allows a user to screen for tissue-specific transcripts across three organisms: human, mouse, and zebrafish. C-It-Loci is very intuitive and easy to use to identify not only protein-coding genes but also ncRNAs from various tissues. C-It-Loci defines homology through sequence and positional conservation to allow for the extraction of species-conserved loci. C-It-Loci can be used as a starting point for further biological experiments. C-It-Loci is freely available online without registration at http://c-it-loci.uni-frankfurt.de. uchida@med.uni-frankfurt.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. © The Author (2015). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Bioinformatics 07/2015; DOI:10.1093/bioinformatics/btv410 · 4.62 Impact Factor
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    ABSTRACT: Identification of subjects at increased risk for cardiovascular events plays a central role in the worldwide efforts to improve prevention, prediction, diagnosis, and prognosis of cardiovascular disease and to decrease the related costs. Despite their high predictive value on population level, traditional risk factors fail to fully predict individual risk. This position paper provides a summary of current vascular biomarkers other than the traditional risk factors with a special focus on the emerging -omics technologies. The definition of biomarkers and the identification and use of classical biomarkers are introduced, and we discuss the limitations of current biomarkers such as high sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). This is complemented by circulating plasma biomarkers, including high-density lipoprotein (HDL), and the conceptual shift from HDL cholesterol levels to HDL composition/function for cardiovascular risk assessment. Novel sources for plasma-derived markers include microparticles, microvesicles, and exosomes and their use for current omics-based analytics. Measurement of circulating micro-RNAs, short RNA sequences regulating gene expression, has attracted major interest in the search for novel biomarkers. Also, mass spectrometry and nuclear magnetic resonance spectroscopy have become key complementary technologies in the search for new biomarkers, such as proteomic searches or identification and quantification of small metabolites including lipids (metabolomics and lipidomics). In particular, pro-inflammatory lipid metabolites have gained much interest in the cardiovascular field. Our consensus statement concludes on leads and needs in biomarker research for the near future to improve individual cardiovascular risk prediction. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    European Heart Journal 06/2015; DOI:10.1093/eurheartj/ehv236 · 14.72 Impact Factor
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    Circulation Research 04/2015; 116(11). 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
  • Jan-H Rohde · Julia E Weigand · Beatrix Suess · Stefanie Dimmeler
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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; 25(3). DOI:10.1089/nat.2014.0501
  • 81. Jahrestagung der Deutsche Gesellschaft für Kardiologie- Herz- und Kreislaufforschung, Mannheim; 04/2015
  • 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 · 3.23 Impact Factor

Publication Stats

46k Citations
3,974.67 Total Impact Points

Institutions

  • 1997–2015
    • Goethe-Universität Frankfurt am Main
      • • Zentrum für Molekulare Medizin
      • • Center for Internal Medicine
      Frankfurt, Hesse, Germany
    • University of Wuerzburg
      • Department of Internal Medicine II
      Würzburg, Bavaria, Germany
  • 2013–2014
    • CardioVasculäres Centrum Frankfurt
      Frankfurt, Hesse, Germany
  • 1997–2011
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 2010
    • Justus-Liebig-Universität Gießen
      • Department of Internal Medicine
      Giessen, Hesse, Germany
  • 2008
    • University of California, San Diego
      • Division of Cardiology
      San Diego, CA, United States
  • 2007
    • Westchester Medical Center
      Valhalla, New York, United States
  • 2005–2007
    • University of Florence
      • Dipartimento di Medicina Sperimentale e Clinica
      Florens, Tuscany, Italy
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2006
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2004
    • University of Hamburg
      Hamburg, Hamburg, Germany
  • 1996
    • University of Cologne
      • Center for Experimental Medicine
      Köln, North Rhine-Westphalia, Germany
    • University of Freiburg
      • Institute of Forensic Medicine
      Freiburg, Baden-Württemberg, Germany
  • 1991–1994
    • Universität Konstanz
      • Molecular Toxicology
      Constance, Baden-Württemberg, Germany