ProfessorThomasThum

Van Aelst LN, Summer G, Li S, Gupta SK, Heggermont W, De Vusser K, Carai P, Naesens M, Van Cleemput J, Van de Werf F, Vanhaecke J, Thum T, Waer M, Papageorgiou AP, Schroen B, Heymans Set al., 2016, RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection., American Journal of Transplantation, Vol: 16, Pages: 99-110, ISSN: 1600-6143

Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR-21, -142-3p, -142-5p, -146a, -146b, -155, -222, -223, and -494 increased during ACR in humans and mice, whereas miR-149-5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune-related diseases. Interestingly, 33 of 70 transcripts function downstream of IL-6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR-155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR-155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR-155, and transcripts, in particular those related to the IL-6 pathway, are promising therapeutic targets to prevent acute allograft rejection.

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Piccoli M-T, Gupta SK, Thum T, 2015, Noncoding RNAs as regulators of cardiomyocyte proliferation and death, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 89, Pages: 59-67, ISSN: 0022-2828

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• Citations: 47

Kunz M, Xiao K, Liang C, Viereck J, Pachel C, Frantz S, Thum T, Dandekar Tet al., 2015, Bioinformatics of cardiovascular miRNA biology, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 89, Pages: 3-10, ISSN: 0022-2828

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• Citations: 24

Soerensen-Zender I, Bhayana S, Susnik N, Rolli V, Batkai S, Baisantry A, Bahram S, Sen P, Teng B, Lindner R, Schiffer M, Thum T, Melk A, Haller H, Schmitt Ret al., 2015, Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 26, Pages: 2659-2668, ISSN: 1046-6673

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• Citations: 29

Derda AA, Thum S, Lorenzen JM, Bavendiek U, Heineke J, Keyser B, Stuhrmann M, Givens RC, Kennel PJ, Schulze PC, Widder JD, Bauersachs J, Thum Tet al., 2015, Blood-based microRNA signatures differentiate various forms of cardiac hypertrophy, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 196, Pages: 115-122, ISSN: 0167-5273

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• Citations: 76

Heymans S, Gonzalez A, Pizard A, Papageorgiou AP, Lopez-Andres N, Jaisser F, Thum T, Zannad F, Diez Jet al., 2015, Searching for new mechanisms of myocardial fibrosis with diagnostic and/or therapeutic potential, EUROPEAN JOURNAL OF HEART FAILURE, Vol: 17, Pages: 764-771, ISSN: 1388-9842

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• Citations: 99

Mayer SC, Gilsbach R, Preissl S, Ordonez EBM, Schnick T, Beetz N, Lother A, Rommel C, Ihle H, Bugger H, Ruehle F, Schrepper A, Schwarzer M, Heilmann C, Boenisch U, Gupta SK, Wilpert J, Kretz O, von Elverfeldt D, Orth J, Aktories K, Beyersdorf F, Bode C, Stiller B, Krueger M, Thum T, Doenst T, Stoll M, Hein Let al., 2015, Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure, Circulation Research, Vol: 117, Pages: 622-633, ISSN: 1524-4571

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Devaux Y, Zangrando J, Schroen B, Creemers EE, Pedrazzini T, Chang C-P, Dorn GW, Thum T, Heymans Set al., 2015, Long noncoding RNAs in cardiac development and ageing, NATURE REVIEWS CARDIOLOGY, Vol: 12, Pages: 415-425, ISSN: 1759-5002

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• Citations: 247

Dangwal S, Stratmann B, Bang C, Lorenzen JM, Kumarswamy R, Fiedler J, Falk CS, Scholz CJ, Thum T, Tschoepe Det al., 2015, Impairment of Wound Healing in Patients With Type 2 Diabetes Mellitus Influences Circulating MicroRNA Patterns via Inflammatory Cytokines, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 35, Pages: 1480-1488, ISSN: 1079-5642

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• Citations: 101

Lorenzen JM, Schauerte C, Huebner A, Koelling M, Martino F, Scherf K, Batkai S, Zimmer K, Foinquinos A, Kaucsar T, Fiedler J, Kumarswamy R, Bang C, Hartmann D, Gupta SK, Kielstein J, Jungmann A, Katus HA, Weidemann F, Mueller OJ, Haller H, Thum Tet al., 2015, Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis, European Heart Journal, Vol: 36, Pages: 2184-2196, ISSN: 1522-9645

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Viereck J, Kumarswamy R, Thum T, 2015, Long Noncoding RNAs as Inducers and Terminators of Vascular Development, CIRCULATION, Vol: 131, Pages: 1236-1238, ISSN: 0009-7322

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• Citations: 5

Hirt MN, Werner T, Indenbirken D, Alawi M, Demin P, Kunze A-C, Stenzig J, Starbatty J, Hansen A, Fiedler J, Thum T, Eschenhagen Tet al., 2015, Deciphering the microRNA signature of pathological cardiac hypertrophy by engineered heart tissue- and sequencing-technology, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 81, Pages: 1-9, ISSN: 0022-2828

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• Citations: 37

Zwadlo C, Schmidtmann E, Szaroszyk M, Kattih B, Froese N, Hinz H, Schmitto JD, Widder J, Batkai S, Baehre H, Kaever V, Thum T, Bauersachs J, Heineke Jet al., 2015, Antiandrogenic Therapy With Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction, CIRCULATION, Vol: 131, Pages: 1071-1081, ISSN: 0009-7322

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• Citations: 56

Watson CJ, Gupta SK, O'Connell E, Thum S, Glezeva N, Fendrich J, Gallagher J, Ledwidge M, Grote-Levi L, McDonald K, Thum Tet al., 2015, MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure, European Journal of Heart Failure, Vol: 17, Pages: 405-415, ISSN: 1879-0844

AimsDifferentiation of heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction independent of echocardiography is challenging in the community. Diagnostic strategies based on monitoring circulating microRNA (miRNA) levels may prove to be of clinical value in the near future. The aim of this study was to identify a novel miRNA signature that could be a useful HF diagnostic tool and provide valuable clinical information on whether a patient has HFrEF or HFpEF.Methods and resultsMiRNA biomarker discovery was carried out on three patient cohorts, no heart failure (no-HF), HFrEF, and HFpEF, using Taqman miRNA arrays. The top five miRNA candidates were selected based on differential expression in HFpEF and HFrEF (miR-30c, −146a, −221, −328, and −375), and their expression levels were also different between HF and no-HF. These selected miRNAs were further verified and validated in an independent cohort consisting of 225 patients. The discriminative value of BNP as a HF diagnostic could be improved by use in combination with any of the miRNA candidates alone or in a panel. Combinations of two or more miRNA candidates with BNP had the ability to improve significantly predictive models to distinguish HFpEF from HFrEF compared with using BNP alone (area under the receiver operating characteristic curve >0.82).ConclusionThis study has shown for the first time that various miRNA combinations are useful biomarkers for HF, and also in the differentiation of HFpEF from HFrEF. The utility of these biomarker combinations can be altered by inclusion of natriuretic peptide. MiRNA biomarkers may support diagnostic strategies in subpopulations of patients with HF.

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Thum T, Condorelli G, 2015, Long Noncoding RNAs and MicroRNAs in Cardiovascular Pathophysiology, CIRCULATION RESEARCH, Vol: 116, Pages: 751-762, ISSN: 0009-7330

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• Citations: 307

Lorenzen JM, Schauerte C, Kielstein T, Huebner A, Martino F, Fiedler J, Gupta SK, Faulhaber-Walter R, Kumarswamy R, Hafer C, Haller H, Fliser D, Thum Tet al., 2015, Circulating Long Noncoding RNA TapSAKI Is a Predictor of Mortality in Critically Ill Patients with Acute Kidney Injury, CLINICAL CHEMISTRY, Vol: 61, Pages: 191-201, ISSN: 0009-9147

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• Citations: 100

Varga ZV, Giricz Z, Bencsik P, Madonna R, Gyoengyoesi M, Schulz R, Mayr M, Thum T, Puskas LG, Ferdinandy Pet al., 2015, Functional Genomics of Cardioprotection by Ischemic Conditioning and the Influence of Comorbid Conditions: Implications in Target Identification, CURRENT DRUG TARGETS, Vol: 16, Pages: 904-911, ISSN: 1389-4501

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• Citations: 39

Li X-G, Roivainen A, Bergman J, Heinonen A, Bengel F, Thum T, Knuuti Jet al., 2015, Enabling [<SUP>18</SUP>F]-bicyclo[6.1.0]nonyne for oligonucleotide conjugation for positron emission tomography applications: [<SUP>18</SUP>F]-anti-microRNA-21 as an example, CHEMICAL COMMUNICATIONS, Vol: 51, Pages: 9821-9824, ISSN: 1359-7345

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• Citations: 12

Kumarswamy R, Volkmann I, Beermann J, Napp LC, Jabs O, Bhayadia R, Melk A, Ucar A, Chowdhury K, Lorenzen JM, Gupta SK, Batkai S, Thum Tet al., 2014, Vascular importance of themiR-212/132 cluster, EUROPEAN HEART JOURNAL, Vol: 35, Pages: 3224-3231, ISSN: 0195-668X

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• Citations: 68

Batkai S, Thum T, 2014, Towards novel theranostic approaches in cardiac transplantation medicine, EUROPEAN HEART JOURNAL, Vol: 35, Pages: 3152-3154, ISSN: 0195-668X

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• Citations: 2

Lorenzen JM, Kaucsar T, Schauerte C, Schmitt R, Rong S, Huebner A, Scherf K, Fiedler J, Martino F, Kumarswamy R, Koelling M, Soerensen I, Hinz H, Heineke J, van Rooij E, Haller H, Thum Tet al., 2014, MicroRNA-24 Antagonism Prevents Renal Ischemia Reperfusion Injury, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 25, Pages: 2717-2729, ISSN: 1046-6673

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• Citations: 112

Sassi Y, Ahles A, Truong D-JJ, Baqi Y, Lee S-Y, Husse B, Hulot J-S, Foinquinos A, Thum T, Mueller CE, Dendorfer A, Laggerbauer B, Engelhardt Set al., 2014, Cardiac myocyte-secreted cAMP exerts paracrine action via adenosine receptor activation, JOURNAL OF CLINICAL INVESTIGATION, Vol: 124, Pages: 5385-5397, ISSN: 0021-9738

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• Citations: 61

Thum T, 2014, Noncoding RNAs and myocardial fibrosis, NATURE REVIEWS CARDIOLOGY, Vol: 11, Pages: 655-663, ISSN: 1759-5002

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• Citations: 152

Radke RM, Diller G-P, Duck M, Orwat S, Hartmann D, Thum T, Baumgartner Het al., 2014, Endothelial function in contemporary patients with repaired coarctation of aorta, HEART, Vol: 100, Pages: 1696-1701, ISSN: 1355-6037

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• Citations: 16

John K, Hadem J, Krech T, Wahl K, Manns MP, Dooley S, Batkai S, Thum T, Schulze-Osthoff K, Bantel Het al., 2014, MicroRNAs Play a Role in Spontaneous Recovery From Acute Liver Failure, HEPATOLOGY, Vol: 60, Pages: 1346-1355, ISSN: 0270-9139

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• Citations: 71

Fiedler J, Stoehr A, Gupta SK, Hartmann D, Holzmann A, Just A, Hansen A, Hilfiker-Kleiner D, Eschenhagen T, Thum Tet al., 2014, Functional MicroRNA Library Screening Identifies the HypoxaMiR MiR-24 as a Potent Regulator of Smooth Muscle Cell Proliferation and Vascularization, ANTIOXIDANTS & REDOX SIGNALING, Vol: 21, Pages: 1167-1176, ISSN: 1523-0864

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• Citations: 36

Thum T, 2014, Non-coding RNAs in ageing, AGEING RESEARCH REVIEWS, Vol: 17, Pages: 1-2, ISSN: 1568-1637

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• Citations: 6

Gupta SK, Piccoli MT, Thum T, 2014, Non-coding RNAs in cardiovascular ageing, AGEING RESEARCH REVIEWS, Vol: 17, Pages: 79-85, ISSN: 1568-1637

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• Citations: 26

Osipova J, Fischer D-C, Dangwal S, Volkmann I, Widera C, Schwarz K, Lorenzen JM, Schreiver C, Jacoby U, Heimhalt M, Thum T, Haffner Det al., 2014, Diabetes-Associated MicroRNAs in Pediatric Patients With Type 1 Diabetes Mellitus: A Cross-Sectional Cohort Study, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 99, Pages: E1661-E1665, ISSN: 0021-972X

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• Citations: 110

Batkai S, Thum T, 2014, Analytical approaches in microRNA therapeutics, JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, Vol: 964, Pages: 146-152, ISSN: 1570-0232

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• Citations: 14