German Center for Cardiovascular Research

Göttingen, Germany

German Center for Cardiovascular Research

Göttingen, Germany
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Schulz C.,Ludwig Maximilians University of Munich | Schulz C.,German Center for Cardiovascular Research | Massberg S.,Ludwig Maximilians University of Munich | Massberg S.,German Center for Cardiovascular Research
Science Translational Medicine | Year: 2014

Atherosclerosis is a chronic inflammatory disease that manifests in multiple vascular beds and frequently culminates in ischemic events, including myocardial infarction. Blood monocytes that are recruited to the inflamed vascular wall develop into inflammatory macrophages and foam cells, which contribute to pathogenesis at many stages of this disease and, therefore, represent a target for therapeutic interventions. Recently, alternate sources of macrophages have been identified. Here, we discuss the origin and molecular regulation of macrophages and highlight recent conceptual changes that may shape the development of effective treatments.

News Article | December 21, 2016

Diet-related diseases like non-alcoholic fatty liver disease (NAFLD) are known to have a major inflammatory component. However, the molecular pathways linking diet-induced changes with inflammation remained elusive. In a new study, scientists at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna identified crucial inflammatory processes in NAFLD. Moreover, the study published in Hepatology shows that malondialdehyde (MDA), a biomarker for oxidative stress, plays a key role in the development of NAFLD and can be neutralized by specific natural antibodies - a novel approach towards a potential therapy for the prevalent disease. The combination of a nutrient rich, western diet and a lack of exercise is a lifestyle which can lead to serious health issues: Worldwide, the incidences of obesity, hypertension or insulin resistance are alarmingly high. As a consequence, risk of developing inflammation-associated diseases like type 2 diabetes, NAFLD and cardiovascular disease increased accordingly. However, the exact pathways that link the eating habits with the ensuing inflammation were so far not well understood. The team of Christoph Binder, Professor of Atherosclerosis Research at the Medical University of Vienna and Principal Investigator at CeMM, in collaboration with Ronit Shiri-Sverdlov at the Maastricht University, Christoph Reinhardt at the University Medical Center of the Johannes Gutenberg University Mainz and the German Center for Cardiovascular Research Mainz was not only able to shed light on the biological processes that lead to the development of chronic inflammation upon a nutrient rich diet in mice. Moreover, the scientists found MDA to be a key player in hepatic inflammation which can be neutralized with natural antibodies. Their results were published in Hepatology (DOI: 10.1002/hep.28970). The highly reactive molecule malondialdehyde, a product from lipid decomposition and biomarker for oxidative stress, accumulates on the surface of dying cells in the liver. Chemically bound to membrane proteins or phospholipids, they form so called MDA epitopes - Binder's research group showed that those MDA epitopes induce cytokine secretion as well as leukocyte recruitment and thereby propagate existing inflammation and render it chronic. "We were able to show in cell culture as well as in model organisms that those MDA epitopes play a major role in diet-induced hepatic inflammation," says Clara Jana-Lui Busch, one of the co-first authors of the study and PhD student at CeMM and the Medical University of Vienna. This was not the only insight of the study: "With intravenous injection of a specific MDA antibody which binds MDA epitopes selectively, we could ameliorate the inflammation in mice" Tim Hendrikx, the other co-first author and PostDoc in the group of Christoph Binder adds. This study shows how the close collaboration of CeMM and the Medical University of Vienna fosters the development of a future precision medicine, says senior author Christoph Binder. "With cutting edge RNA sequencing methods and bioinformatic analyses of transcriptome data, we discovered key mechanisms in some of the most prevalent diseases and we confirmed those findings in mice models." Binder explains, and adds: "Above that, the administration of specific antibodies for MDA epitopes provide a promising new approach for the development of therapeutic strategies." The study "Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice" was published in Hepatology online in advance on December 16 2016. DOI: 10.1002/hep.28970 The study was funded by The Austrian Science Fund (FWF, SFB Lipotox F30), Boehringer Ingelheim (PhD Fellowship), Austrian Academy of Sciences (Doc Fellowship), EMBO (Short Term Fellowships), The Netherlands Organisation for Scientific Research (NWO), German Center for Cardiovascular Research (DZHK), German Federal Ministry of Education and Research, and the German Research Foundation (DFG). Christoph Binder obtained his MD degree at the University of Vienna in 1997 and received his Ph.D. in Molecular Pathology at the University of California San Diego (UCSD) in 2002. Following a postdoctoral training period at UCSD, he joined the Institute for Laboratory Medicine of the Medical University of Vienna and became Principal Investigator at CeMM in 2006. In 2009 he was appointed Professor of Atherosclerosis Research at the Medical University of Vienna. Christoph Binder is dually affiliated with CeMM and the Medical University of Vienna. http://cemm. The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an interdisciplinary research institute committed to advancing the understanding of human diseases through basic and biomedical research. Located at the center of the Medical University of Vienna's campus, CeMM fosters a highly collaborative and interactive research mindset. Focusing on medically relevant questions, CeMM researchers concentrate on human biology and diseases like cancer and inflammation/immune disorders. In support of scientific pursuits and medical needs, CeMM provides access to cutting-edge technologies and has established a strategic interest in personalized medicine. Since 2005, Giulio Superti-Furga is the Scientific Director of CeMM. http://www. The Medical University of Vienna is one of the most traditional medical education establishments with nearly 8,000 students and approximately 5,500 staff members, and one of the most important top-level biomedical research institutions in Europe. Its international outlook is one of its most important pillars and the research focus is centered on immunology, cancer research, imaging, brain research and cardiovascular diseases. https:/ For further information please contact CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 http://www.

Drews O.,University of Heidelberg | Drews O.,German Center for Cardiovascular Research | Taegtmeyer H.,University of Houston
Antioxidants and Redox Signaling | Year: 2014

Significance: Novel therapeutic strategies to treat heart failure are greatly needed. The ubiquitin-proteasome system (UPS) affects the structure and function of cardiac cells through targeted degradation of signaling and structural proteins. This review discusses both beneficial and detrimental consequences of modulating the UPS in the heart. Recent Advances: Proteasome inhibitors were first used to test the role of the UPS in cardiac disease phenotypes, indicating therapeutic potential. In early cardiac remodeling and pathological hypertrophy with increased proteasome activities, proteasome inhibition prevented or restricted disease progression and contractile dysfunction. Conversely, enhancing proteasome activities by genetic manipulation, pharmacological intervention, or ischemic preconditioning also improved the outcome of cardiomyopathies and infarcted hearts with impaired cardiac and UPS function, which is, at least in part, caused by oxidative damage. Critical Issues: An understanding of the UPS status and the underlying mechanisms for its potential deregulation in cardiac disease is critical for targeted interventions. Several studies indicate that type and stage of cardiac disease influence the dynamics of UPS regulation in a nonlinear and multifactorial manner. Proteasome inhibitors targeting all proteasome complexes are associated with cardiotoxicity in humans. Furthermore, the type and dosage of proteasome inhibitor impact the pathogenesis in nonuniform ways. Future Directions: Systematic analysis and targeting of individual UPS components with established and innovative tools will unravel and discriminate regulatory mechanisms that contribute to and protect against the progression of cardiac disease. Integrating this knowledge in drug design may reduce adverse effects on the heart as observed in patients treated with proteasome inhibitors against noncardiac diseases, especially cancer. © 2014 Mary Ann Liebert, Inc.

Ye L.,University of Minnesota | Ye L.,University of Gottingen | Zimmermann W.-H.,German Center for Cardiovascular Research | Garry D.J.,University of Minnesota | Zhang J.,University of Minnesota
Circulation Research | Year: 2013

Transplantation of engineered tissue patches containing either progenitor cells or cardiomyocytes for cardiac repair is emerging as an exciting treatment option for patients with postinfarction left ventricular remodeling. The beneficial effects may evolve directly from remuscularization or indirectly through paracrine mechanisms that mobilize and activate endogenous progenitor cells to promote neovascularization and remuscularization, inhibit apoptosis, and attenuate left ventricular dilatation and disease progression. Despite encouraging results, further improvements are necessary to enhance current tissue engineering concepts and techniques and to achieve clinical impact. Herein, we review several strategies for cardiac remuscularization and paracrine support that can induce cardiac repair and attenuate left ventricular dysfunction from both within and outside the myocardium. © 2013 American Heart Association, Inc.

Viola J.,Ludwig Maximilians University of Munich | Soehnlein O.,Ludwig Maximilians University of Munich | Soehnlein O.,Academic Medical Center | Soehnlein O.,German Center for Cardiovascular Research
Seminars in Immunology | Year: 2015

Atherosclerosis is commonly looked upon as a chronic inflammatory disease of the arterial wall arising from an unbalanced lipid metabolism and a maladaptive inflammatory response. However, atherosclerosis is not merely an inflammation of the vessel wall. In fact, the cardinal signs of unstable atherosclerotic lesions are primarily characteristics of failed resolution of a chronic inflammation. In contrast to acute inflammatory events which are typically self-limiting, atherosclerosis is an unresolved inflammatory condition, lacking the switch from the pro-inflammatory to the pro-resolving phase, the latter characterized by termination of inflammatory cell recruitment, removal of inflammatory cells from the site of inflammation by apoptosis and dead cell clearance, reprogramming of macrophages toward an anti-inflammatory, regenerative phenotype, and finally egress of effector cells and tissue regeneration. Here we present an overview on mechanisms of failed resolution contributing to atheroprogression and deliver a summary of novel therapeutic strategies to restore resolution in inflamed arteries. © 2015 Elsevier Ltd.

Zeisberg E.M.,University of Gottingen | Zeisberg E.M.,German Center for Cardiovascular Research | Zeisberg M.,University of Gottingen
Journal of Pathology | Year: 2013

The aberrant methylation of CpG island promoters of selected genes is the prominent epigenetic mechanism by which gene transcription can be effectively silenced. Aberrant hypermethylation of a few selected genes plays an important role in facilitating fibrotic fibroblast activation and in driving fibrogenesis. Here we review mechanisms of DNA methylation and demethylation and their implications for fibroblast activation and tissue fibrosis.Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Zernecke A.,University of Würzburg | Zernecke A.,TU Munich | Zernecke A.,German Center for Cardiovascular Research | Weber C.,German Center for Cardiovascular Research | Weber C.,Ludwig Maximilians University of Munich
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

Chemokines play important roles in atherosclerotic vascular disease. Expressed by not only cells of the vessel wall but also emigrated leukocytes, chemokines were initially discovered to direct leukocytes to sites of inflammation. However, chemokines can also exert multiple functions beyond cell recruitment. Here, we discuss novel and recently emerging aspects of chemokines and their involvement in atherosclerosis. While reviewing newly identified roles of chemokines and their receptors in monocyte and neutrophil recruitment during atherogenesis and atheroregression, we also revisit homeostatic functions of chemokines, including their roles in cell homeostasis and foam cell formation. The functional diversity of chemokines in atherosclerosis warrants a clear-cut mechanistic dissection and stage-specific assessment to better appreciate the full scope of their actions in vascular inflammation and to identify pathways that harbor the potential for a therapeutic targeting of chemokines in atherosclerosis. © 2014 American Heart Association, Inc.

Alfonso F.,Hospital Universitario La Paz | Byrne R.A.,TU Munich | Byrne R.A.,German Center for Cardiovascular Research | Rivero F.,Hospital Universitario La Paz | And 2 more authors.
Journal of the American College of Cardiology | Year: 2014

Management of patients with in-stent restenosis (ISR) remains an important clinical problem. Although drug-eluting stents (DES) have drastically reduced the incidence of ISR, treatment of DES-ISR is particularly challenging. ISR mainly results from aggressive neointimal proliferation, but recent data also suggest that neoatherosclerosis may play an important pathophysiological role. Intracoronary imaging provides unique insights to unravel the underlying substrate of ISR and may be used to guide repeated interventions. In this paper, we systematically reviewed clinical trial data with currently available therapeutic modalities, including DES and drug-coated balloons, in patients presenting with ISR within bare-metal stents or DES. © 2014 by the American College of Cardiology Foundation.

Uchida S.,Goethe University Frankfurt | Uchida S.,German Center for Cardiovascular Research | Dimmeler S.,Goethe University Frankfurt | Dimmeler S.,German Center for Cardiovascular Research
Circulation Research | Year: 2015

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.

Dimmeler S.,Goethe University Frankfurt | Dimmeler S.,German Center for Cardiovascular Research | Nicotera P.,German Center for Neurodegenerative Diseases
EMBO Molecular Medicine | Year: 2013

Aging is a complex process that is linked to an increased incidence of major diseases such as cardiovascular and neurodegenerative disease, but also cancer and immune disorders. MicroRNAs (miRNAs) are small non-coding RNAs, which post-transcriptionally control gene expression by inhibiting translation or inducing degradation of targeted mRNAs. MiRNAs target up to hundreds of mRNAs, thereby modulating gene expression patterns. Many miRNAs appear to be dysregulated during cellular senescence, aging and disease. However, only few miRNAs have been so far linked to age-related changes in cellular and organ functions. The present article will discuss these findings, specifically focusing on the cardiovascular and neurological systems. This review is part of the small RNAs review series. See more reviews from this series. MicroRNAs have been implicated in the aging process. This review discusses recent findings on the roles of microRNAs in conditions associated with aging, with a focus on cardiovascular and neurodegenerative diseases. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

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