Stefanie Dimmeler

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

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Publications (446)4116.99 Total impact

  • No preview · Article · Jan 2016 · Journal of Molecular Cell Biology
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    ABSTRACT: Aims: Regenerative therapies have evolved as a promising new option in the treatment of post-infarction heart failure. A major limitation of intracoronary application of autologous bone marrow-derived mononuclear cells (BM-MNCs) is that homing of the applied cells is profoundly reduced in patients with post-infarction heart failure compared with patients with acute myocardial infarction. However, early pilot and also randomized controlled trials have demonstrated significant improvements in overall cardiac function. The aim of the present analysis was to quantify a potential mortality risk reduction and reduced hospitalization in order to provide data for a prospective outcome trial. Methods and results: The results of an ongoing single-centre registry including 297 post-infarction heart failure patients suggest that repeated intracoronary application of autologous bone marrow-derived cells is associated with a significant better 2-year survival compared with a single BM-MNC application (2-year survival 93.6 vs. 84.0%, P = 0.03). Likewise, mortality is significantly lower at 2-year follow-up compared with the mortality estimated by the use of the Seattle Heart Failure Model (SHFM) in patients receiving repeated BM-MNC application (observed mortality 6.4%, predicted mortality 16.2%, P = 0.02). Although the trend persisted at 3-year follow-up, the mortality reduction was no longer statistically significant between single and repeated treatment (mortality 21.9 vs. 13.7%, P = 0.06). Conclusion: Repeated intracoronary administration of BM-MNC appears to be associated with improved clinical outcome compared with single treatment at 2 years. This registry provides the rationale for the design of the multicentre randomized, controlled, open-label REPEAT trial, which prospectively compares the effects of single vs. repeated intracoronary application of autologous BM-MNC on total and SHFM-predicted mortality in patients with chronic post-infarction heart failure.
    No preview · Article · Oct 2015 · European Heart Journal
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    ABSTRACT: MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression. Laminar blood flow induces atheroprotective gene expression in endothelial cells (ECs) in part by upregulating the transcription factor KLF2. Here, we identified KLF2- and flow-responsive miRs that affect gene expression in ECs. Bioinformatic assessment of mRNA expression patterns identified the miR-30-5p seed sequence to be highly enriched in mRNAs that are downregulated by KLF2. Indeed, KLF2 overexpression and shear stress stimulation in vitro and in vivo increased the expression of miR-30-5p family members. Furthermore, we identified angiopoietin 2 (Ang2) as a target of miR-30. MiR-30 overexpression reduces Ang2 levels, whereas miR-30 inhibition by LNA-antimiRs induces Ang2 expression. Consistently, miR-30 reduced basal and TNF-a-induced expression of the inflammatory cell-cell adhesion molecules E-selectin, ICAM1 and VCAM1, which was rescued by stimulation with exogenous Ang2. In summary, KLF2 and shear stress increase the expression of the miR-30-5p family which acts in an antiinflammatory manner in ECs by impairing the expression of Ang2 and inflammatory cell-cell adhesion molecules. The upregulation of miR-30-5p family members may contribute to the atheroprotective effects of shear stress.
    No preview · Article · Oct 2015 · Journal of Molecular and Cellular Cardiology
  • Judy Ozkan · Stefanie Dimmeler

    No preview · Article · Oct 2015 · European Heart Journal
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    ABSTRACT: Rationale: Circular RNAs (circRNAs) are non-coding RNAs generated by back-splicing. Back-splicing has been considered a rare event, but recent studies suggest that circRNAs are widely expressed. However, the expression, regulation and function of circRNAs in vascular cells is still unknown. Objective: Here, we characterize the expression, regulation and function of circRNAs in endothelial cells. Methods and Results: Endothelial circRNAs were identified by computational analysis of ribo-minus RNA generated from human umbilical venous endothelial cells cultured under normoxic or hypoxic conditions. Selected circRNAs were biochemically characterized, and we found that the majority of them lacks polyadenylation, is resistant to RNase R digestion and localized to the cytoplasm. We further validated the hypoxia-induced circRNAs cZNF292, cAFF1, and cDENND4C as well as the down-regulated cTHSD1 by RT-PCR in cultured endothelial cells. Cloning of cZNF292 validated the predicted back splicing of exon 4 to a new alternative exon 1A. Silencing of cZNF292 inhibited cZNF292 expression and reduced tube formation and spheroid sprouting of endothelial cells in vitro. The expression of pre-mRNA or mRNA of the host gene was not affected by silencing of cZNF292. No validated miRNA binding sites for cZNF292 were detected in Argonaute HITS-CLIP data sets, suggesting that cZNF292 does not act as a microRNA sponge. Conclusions: We show that the majority of the selected endothelial circRNAs fulfill all criteria of bona fide circRNAs. The circRNA cZNF292 exhibits pro-angiogenic activities in vitro. These data suggest that endothelial circRNAs are regulated by hypoxia and have biological functions.
    No preview · Article · Sep 2015 · Circulation Research
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    ABSTRACT: By transporting regulatory RNAs like microRNAs, extracellular vesicles provide a novel layer of intercellular gene regulation. However, the underlying secretory pathways and the mechanisms of cargo selection are poorly understood. Rab GTPases are central coordinators of membrane trafficking with distinct members of this family being responsible for specific transport pathways. Here we identified a vesicular export mechanism for miR-143, induced by the shear stress responsive transcription factor KLF2, and demonstrate its dependency on Rab7a / Rab27b in endothelial cells.
    Full-text · Article · Sep 2015 · FEBS letters
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    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:
    No preview · Article · Aug 2015 · Briefings in Bioinformatics
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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.
    No preview · Article · Aug 2015 · European Respiratory Journal
  • 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 SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. © The Author (2015). Published by Oxford University Press. All rights reserved. For Permissions, please email:
    No preview · Article · Jul 2015 · Bioinformatics
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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:
    Full-text · Article · Jun 2015 · European Heart Journal
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    Full-text · Article · Apr 2015 · Circulation Research
  • Birgit Assmus · Stefanie Dimmeler · Andreas M Zeiher

    No preview · Article · Apr 2015 · Circulation Research
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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.
    Full-text · Article · Apr 2015 · Cellular Microbiology
  • 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.
    No preview · Article · Apr 2015 · Cell metabolism
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    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.
    Preview · Article · Apr 2015

  • No preview · Conference Paper · Apr 2015
  • Nicolas Jaé · Stefanie Dimmeler

    No preview · Article · Mar 2015 · Circulation Research
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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.
    Full-text · Article · Mar 2015 · Journal of the American College of Cardiology
  • 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.
    No preview · Article · Feb 2015 · Circulation Research
  • 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.
    No preview · Article · Dec 2014 · Nature Reviews Cardiology

Publication Stats

51k Citations
4,116.99 Total Impact Points


  • 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
  • 2012-2013
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany
  • 2011-2013
    • 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
  • 2006
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2005
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
    • University of Florence
      • Dipartimento di Medicina Sperimentale e Clinica
      Florens, Tuscany, Italy
  • 1996
    • University of Freiburg
      • Institute of Forensic Medicine
      Freiburg, Baden-Württemberg, Germany
  • 1995-1996
    • University of Cologne
      • Center for Experimental Medicine
      Köln, North Rhine-Westphalia, Germany
  • 1991-1994
    • Universität Konstanz
      • Molecular Toxicology
      Constance, Baden-Württemberg, Germany