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Junior Research Group E-31

Title

Cardiac Wounding and Healing

Project Leader

Thomas Thum, MD, PhD
Medizinische Klink I / Kardiologie

Research focus

Diseases of the cardiovascular system are a primary and most common cause of human morbidity and mortality in the industrialized nations (European World Health Organisation, WHO). The costs per year of cardiovascular diseases to the European health care system are estimated to be as high as 192 milliards of Euro per year (www.cordis.europa.eu). Although classic pharmacological treatment strategies have improved cardiovascular outcome and survival of heart failure patients (e.g. Beta-Blockers and ACE-inhibitors), the prognosis of affected individuals remains poor with about 1.9 million cardiovascular deaths in the European Union per year.

 

This highlights the need for innovative novel therapies for heart diseases. A variety of cardiovascular diseases, such as coronary artery disease, hypertension, myocardial infarction, myocarditis and genetic forms of cardiomyopathies result in a phenoytypic similar endpoint, viz. heart failure. Therefore, the search for basic mechanisms that are involved in the development and progression of heart failure has been exhaustive, but unfortunately direct mechanistic and effective therapies are not available.

 

Understanding cardiac regeneration after myocardial infarction is a fascinating avenue to explore. Potential options include use of cells with pluripotency such as embryonic or adult stem cells. We have developed methods to isolate and cultivate human stem cells towards cardiovascular cells. Under main focus are investigations regarding number and function of endothelial progenitor cells (EPCs) in various cardiovascular diseases (J Am Coll Cardiol. 2005, 46, 1693-1701; Circ Res, 2007, 100:434-443; Diabetes, 2007, 56:666-674). We explore molecular mechanisms regulating the differentiation of stem cells to various cardiovascular cells to finally develop better cell-based therapeutic approaches for cardiac healing.

 

Recent studies have uncovered important and unexpected roles for a family of small regulatory RNA molecules, known as microRNAs (miRNAs) in the regulation of diverse aspects of cardiac function (Cardiovasc Res, 2008, 79:562-70). We found distinct sets of miRNAs to be altered during cardiac hypertrophy, that re-activate a fetal gene program in heart failure (Circulation, 2007, 116:258-67). We also explore the role of miRNAs during differentiation of human progenitor cells to mature cardiovascular cells, e.g. cardiomyocytes and endothelial cells. Chemically engineered oligonucleotides, termed “antagomirs” have been developed and proven to be efficient and specific silencers of endogenous miRNAs in mice. Our group has developed a novel therapeutic strategy to use miRNA antagonists in cardiac disease to inhibit cardiac fibrosis and thus demonstrated principle suitability of such miRNA-based approaches (Thum et al., Nature, 2008, in press).

 

We aim in our group to understand how miRNAs orchestrate the complex genetic networks in individual cells important for cardiovascular homeostasis and disease. This indeed may allow us to specifically target single or combinations of miRNAs to improve therapy of cardiovascular diseases such as cardiac hypertrophy, fibrosis and failure. A fundamental understanding of the role of miRNAs in the control of gene expression may represent a unique opportunity to develop novel miRNA-based therapeutic strategies for cardiac disease.

Project duration

2006-2011

Grant support

Ernst-und Berta Grimmke Stiftung;  Regulation of endothelial progenitor cell function

Novartis-Foundation; Dysfunction of endothelial progenitor cells during cardiovascular disease

Interdisciplinary Center for Clinical Research Würzburg, Research Group Cardiac Wounding and Healing (E31).

German Research Foundation (DFG); Vascular microRNAs

Cooperations

Extra-universitary cooperations:

Fraunhofer Institute ITEM, Hannover

Clin. Pharmacology, Hannover Medical School

Cardiovascular Medicine, Stanford University, USA

NHLI, Imperial College London, UK

Cardiology, Charite Berlin

Cardiology, University of Homburg

Cardiology, University of Hamburg

Cardiology, Universität of Mainz

Hubrechts Lab, Utrecht, Netherlands

 

Intra-universitary cooperations:

Prof. Dr. J. Bauersachs, Cardiology

Prof. Dr. C. Wanner, Nephrology

Prof. Dr. B. Allolio, Endocrinology

Prof. Dr. Dr. S. Engelhardt, Technical University Munich

Publications

2008


 

Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Just S, Rottbauer W, Bussen M, Galuppo P, Frantz S, Castoldi M, Muckenthaler M, Soutschek J, Koteliansky, Rosenwald A, Pena JT, Tuschl T, Martin GR, Bauersachs J, Engelhardt S. (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAPkinase signalling in fibroblasts. Nature (in press).

 

Thum T and Bauersachs J (2008) MicroRNAs in cardiac hypertrophy and failure. Drug Discovery Today (in press).

 

Thum T. (2008) Cardiac dissonance without conductors – How dicer depletion provokes chaos in the heart. Circulation 118:1524-7.

 

Thum T, Catalucci D, Bauersachs J. (2008) MicroRNAs: novel regulators in cardiac development and disease. Cardiovasc Res 79:562-70.

 

Thum T and Borlak J. (2008) LOX-1 receptor blockade abrogates oxLDL induced oxidative DNA damage and prevents activation of the transcriptional repressor Oct-1 in human coronary arterial endothelial cells. J Biol Chem 283:19456-64.

 

Fraccarollo D, Widder, JD, Galuppo P, Thum T, Tsikas D, Hoffmann, M. Ruetten H, Ertl G, Bauersachs, J. (2008) Improvement of left ventricular remodeling by the endothelial nitric oxide synthase enhancer AVE9488 after experimental myocardial infarction. Circulation 118:818-27.

 

Fleissner F. and Thum T. (2008) The IGF-1 receptor as novel target to improve endothelial progenitor cell function Mol Med 14:235-7.

 

Werner C, Hanhoun M, Widmann T, Kazakov A, Semenov A, Pöss J, Bauersachs J, Thum T, Pfreundschuh M, Müller P, Haendeler J, Böhm M, Laufs U. (2008) Effects of Physical Exercise on Myocardial Telomere Regulating Proteins, Survival Pathways and Apoptosis. J Am Coll Cardiol 52:470-82.

 

Diller GP, van Eijl S, Okonko DO, Howard LS, Ali O, Thum T, Wort SJ, Bédard E, Gibbs JS, Bauersachs J, Hobbs AJ, Wilkins MR, Gatzoulis MA, Wharton J. (2008) Circulating Endothelial Progenitor Cells in Patients with Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension. Circulation 117:3020-30.

 

Jakob M and Thum T. (2007) Recent patents on cardiovascular stem cells. Recent Pat Cardiovasc Drug Discov (3:59-72).

Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, Foldes G, Thum T, Majda J, Banasiak W, Missouris CG, Poole-Wilson PA, Anker SD, Ponikowski P. (2008) Effect of Intravenous Iron Sucrose on Exercise Tolerance in Anemic and Non-anemic Patients with Symptomatic Chronic Heart Failure and Iron Deficiency (FERRIC-HF): A Randomized, Controlled, Observer-blinded Trial. J Am Coll Cardiol, 51, 103-112.

Thum T and Bauersachs J. (2008) Letter regarding article “Oxidant stress impairs In vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus. Restoration by the peroxisome proliferator-activated receptor-agonist rosiglitazone“. Circulation (in press).

 



2007



Bauersachs J and Thum T. (2007) MicroRNAs in the broken heart. Eur J Clin Invest, 37:829-33.

Thum T and Anker SD. (2007) Nutritional iron deficiency: Drawbacks and chances. Lancet, 370, 1906.

Wenzel P, Daiber A, Oelze M, Brandt M; Closs E, Xu J, Thum T, Bauersachs J, Ertl G, Zou MH, Forstermann U, Munzel T. (2007) Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. Atherosclerosis (in press).

Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, Doevendans PA, Mummery CL, Borlak J, Haverich A, Gross C, Engelhardt S, Ertl G, Bauersachs J. (2007) MicroRNAs in the Human Heart: A Clue to Fetal Gene Reprogramming in Heart Failure. Circulation, 116:258-67.

Thum T, Fleissner F, Klink I, Tsikas D, Jakob M, Bauersachs J, Stichtenoth D. (2007) Growth hormone treatment improves markers of systemic nitric oxide bioavailability via insulin-like growth factor-1. J Clin Endocrinol Metab. 92:4172-9.

Kielstein JT, Sydow K, Thum T. Tilarginine in patients with acute myocardial infarction and cardiogenic shock. JAMA. 2007;298:971.

Bauersachs J. and Thum T. (2007) Endothelial progenitor cell dysfunction - Mechanisms and therapeutic approaches. Eur J Clin Invest, 37:603-6.

Frantz S, Tillmanns J, Kuhlencordt PJ, Schmidt I, Adamek A, Dienesch C, Thum T, Gerondakis S, Ertl G, Bauersachs J. (2007) Tissue Specific effects of the nuclear factor kappa B subunit P50 on myocardial ischemia-reperfusion injury. Am J Pathol. 171:507-12.

Thum T, Hoeber S, Froese S, Klink I, Stichtenoth DO, Tsikas D, Galuppo P, Anker SD, Poole-Wilson PA, Borlak J, Ertl G, Bauersachs J. (2007) Age-dependent impairment of endothelial progenitor cells is corrected by growth hormone mediated increase of insulin-like growth factor-1. Circ Res, 100:434-443.

Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, Ertl G and  Bauersachs J (2007) Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes, 56:666-674.

Thum T, Fraccarollo D, Schultheiss M, Froese S, Daiber A, Wenzel P, Munzel T, Ertl G and Bauersachs J. (2007). Effect of long-acting nitrates on endothelial progenitor cells is determined by reactive oxygen species formation. Arterioscler Thromb Vasc Biol, 27:748-754.

Tsikas D, Thum T, Becker T, Pham VV, Chobanyan K, Mitschke A, Beckmann B, Gutzki FM, Bauersachs J, Stichtenoth DO. (2007) Accurate quantification of dimethylamine (DMA) in human urine by gas chromatography-mass spectrometry as pentafluorobenzamide derivative: Evaluation of a relationship between DMA and its precursor asymmetric dimethylarginine (ADMA) in health and disease. J Chrom B, 2007 851:229-39.

Thum T and Bauersachs J. (2007). Microarray-based gene expression profiling as a tool to elucidate cellular responses to nitric oxide. J Chrom B, 51:3-11.

 



2006


Thum T, Fraccarollo D, Galuppo P, Tsikas T, Ertl G and Bauersachs J. (2006). Bone marrow molecular alterations after myocardial infarction: Impact on endothelial progenitor cells. Cardiovasc Res. 70, 50-60.

Thum T and Anker SD (2006). Obesity and risk of myocardial infarction: the INTERHEART study. Lancet, 367, 1051-2.

von Haehling S, Sandek A and Thum T (2006). Annual Meeting of the American Heart Association. Expert Opin Investig Drugs, 15, 563-569.

Thum T and Bauersachs J. (2006) Sports or statins for atheroprotection? New insight from Kruppel-like factor-2. Cardiovasc Res 72:193-195.

Thum T, Erpenbeck VJ, Moeller J, Hohlfeld JM, Krug N and Borlak J. (2006) Expression of xenobiotic metabolising enzymes in different lung compartments of smokers and non-smokers. Environ Health Perspect, 114:1655-61.

 



2005


Thum T and Bauersachs J. (2005) Endothelial progenitor cells as potential drug targets. Curr Drug Targets Cardiovasc Haematol Disord, 5, 277-86.

Bauersachs J, Thum T, Frantz S, Ertl G. (2005) Cardiac regeneration by progenitor cells - bedside before bench? Eur J Clin Invest, 35, 417-420.

Thum T and Bauersachs J. (2005) Mobilisation of bone marrow derived stem cells after myocardial infarction and left ventricular function – Simply effects of optimized drug treatment? Eur Heart J 26:1685.

Thum T, Tsikas T, Stein S, Schultheiss M, Eigenthaler M, Anker SD, Poole-Wilson PA, Ertl G and Bauersachs J. (2005) Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. J Am Coll Cardiol. 46, 1693-1701.

Thum T and Bauersachs J (2005) Growth hormone regulates vascular function - What we know from Bench and Bedside. Eur J Clin Pharmacol 62:29-32.

Thum T and Bauersachs J. (2005) Spotlight on endothelial progenitor cell inhibitors. Vasc Med 10:59-64.

Thum T, Bauersachs J, Poole-Wilson PA, Volk HD, Anker S (2005) The dying stem cell hypothesis -Immune modulation as a novel mechanism for progenitor cell therapy in cardiac muscle. J Am Coll Cardiol, 46, 1799-1802.

Thum T and Bauersachs J. (2005) ADMA, endothelial progenitor cells and cardiovascular risk. Circ Res, 97, 84.

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