TY - JOUR AU - Kucsera, Dániel AU - Ruppert, Mihály AU - Sayour, Viktor Nabil AU - Tóth, Viktória AU - Kovács, Tamás AU - Hegedűs, Zsombor AU - Onódi, Zsófia AU - Fábián, Alexandra AU - Kovács, Attila AU - Radovits, Tamás AU - Merkely, Béla Péter AU - Pacher, Pál AU - Ferdinandy, Péter AU - Varga, Zoltán TI - NASH triggers cardiometabolic HFpEF in aging mice JF - GEROSCIENCE: OFFICIAL JOURNAL OF THE AMERICAN AGING ASSOCIATION (AGE) J2 - GEROSCIENCE VL - 46 PY - 2024 IS - 5 SP - 4517 EP - 4531 PG - 15 SN - 2509-2715 DO - 10.1007/s11357-024-01153-9 UR - https://m2.mtmt.hu/api/publication/34799327 ID - 34799327 N1 - Export Date: 31 August 2025; Cited By: 7 AB - Both heart failure with preserved ejection fraction (HFpEF) and non-alcoholic fatty liver disease (NAFLD) develop due to metabolic dysregulation, has similar risk factors (e.g., insulin resistance, systemic inflammation) and are unresolved clinical challenges. Therefore, the potential link between the two disease is important to study. We aimed to evaluate whether NASH is an independent factor of cardiac dysfunction and to investigate the age dependent effects of NASH on cardiac function. C57Bl/6 J middle aged (10 months old) and aged mice (24 months old) were fed either control or choline deficient (CDAA) diet for 8 weeks. Before termination, echocardiography was performed. Upon termination, organ samples were isolated for histological and molecular analysis. CDAA diet led to the development of NASH in both age groups, without inducing weight gain, allowing to study the direct effect of NASH on cardiac function. Mice with NASH developed hepatomegaly, fibrosis, and inflammation. Aged animals had increased heart weight. Conventional echocardiography revealed normal systolic function in all cohorts, while increased left ventricular volumes in aged mice. Two-dimensional speckle tracking echocardiography showed subtle systolic and diastolic deterioration in aged mice with NASH. Histologic analyses of cardiac samples showed increased cross-sectional area, pronounced fibrosis and Col1a1 gene expression, and elevated intracardiac CD68 + macrophage count with increased Il1b expression. Conventional echocardiography failed to reveal subtle change in myocardial function; however, 2D speckle tracking echocardiography was able to identify diastolic deterioration. NASH had greater impact on aged animals resulting in cardiac hypertrophy, fibrosis, and inflammation. LA - English DB - MTMT ER - TY - JOUR AU - Gergely, Tamás G AU - Kucsera, Dániel AU - Tóth, Viktória AU - Kovács, Tamás AU - Sayour, Viktor Nabil AU - Drobni, Zsófia AU - Ruppert, Mihály AU - Petrovich, Balázs AU - Ágg, Bence AU - Onódi, Zsófia AU - Fekete, Nóra AU - Pállinger, Éva AU - Buzás, Edit Irén AU - Yousif, Laura I. AU - Meijers, Wouter C. AU - Radovits, Tamás AU - Merkely, Béla Péter AU - Ferdinandy, Péter AU - Varga, Zoltán TI - Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment JF - BRITISH JOURNAL OF PHARMACOLOGY J2 - BR J PHARMACOL VL - 180 PY - 2023 IS - 6 SP - 740 EP - 761 PG - 22 SN - 0007-1188 DO - 10.1111/bph.15984 UR - https://m2.mtmt.hu/api/publication/33228693 ID - 33228693 N1 - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary HCEMM-SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary Heart and Vascular Center, Semmelweis University, Budapest, Hungary Pharmahungary Group, Szeged, Hungary MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary Department of Cardiology, Medical Center Groningen, University of Groningen, Groningen, Netherlands Division of Experimental Cardiology, Department of Cardiology, Thorax Center, Erasmus University Medical Center, Rotterdam, Netherlands Cited By :5 Export Date: 8 January 2024 CODEN: BJPCB Correspondence Address: Varga, Z.V.; MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Nagyvárad tér 4, Hungary; email: varga.zoltan@med.semmelweis-univ.hu LA - English DB - MTMT ER - TY - JOUR AU - Gergely, Tamás G AU - Brenner, Gábor AU - Nagy, Regina Norma AU - Sayour, Viktor Nabil AU - Makkos, András AU - Kovácsházi, Csenger AU - Tian, Huimin AU - Schulz, Rainer AU - Giricz, Zoltán AU - Görbe, Anikó AU - Ferdinandy, Péter TI - Effects of Bempedoic Acid in Acute Myocardial Infarction in Rats: No Cardioprotection and No Hidden Cardiotoxicity JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 2 PG - 12 SN - 1661-6596 DO - 10.3390/ijms24021585 UR - https://m2.mtmt.hu/api/publication/33567171 ID - 33567171 N1 - MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, H-1089, Hungary Institute of Physiology, Justus Liebig University Giessen, Giessen, 35390, Germany Pharmahungary Group, Szeged, H-6722, Hungary Export Date: 13 March 2023 Correspondence Address: Görbe, A.; MTA-SE System Pharmacology Research Group, Hungary; email: gorbe.aniko@med.semmelweis-univ.hu AB - Lipid-lowering drugs have been shown to have cardioprotective effects but may have hidden cardiotoxic properties. Therefore, here we aimed to investigate if chronic treatment with the novel lipid-lowering drug bempedoic acid (BA) exerts hidden cardiotoxic and/or cardioprotective effects in a rat model of acute myocardial infarction (AMI). Wistar rats were orally treated with BA or its vehicle for 28 days, anesthetized and randomized to three different groups (vehicle + ischemia/reperfusion (I/R), BA + I/R, and positive control vehicle + ischemic preconditioning (IPC)) and subjected to cardiac 30 min ischemia and 120 min reperfusion. IPC was performed by 3 × 5 min I/R cycles before ischemia. Myocardial function, area at risk, infarct size and arrhythmias were analyzed. Chronic BA pretreatment did not influence cardiac function or infarct size as compared to the vehicle group, while the positive control IPC significantly reduced the infarct size. The incidence of reperfusion-induced arrhythmias was significantly reduced by BA and IPC. This is the first demonstration that BA treatment does not show cardioprotective effect although moderately reduces the incidence of reperfusion-induced arrhythmias. Furthermore, BA does not show hidden cardiotoxic effect in rats with AMI, showing its safety in the ischemic/reperfused heart. LA - English DB - MTMT ER - TY - JOUR AU - Kucsera, Dániel AU - Tóth, Viktória AU - Sayour, Viktor Nabil AU - Kovács, Tamás AU - Gergely, Tamás G AU - Ruppert, Mihály AU - Radovits, Tamás AU - Fábián, Alexandra AU - Kovács, Attila AU - Merkely, Béla Péter AU - Ferdinandy, Péter AU - Varga, Zoltán TI - IL-1β neutralization prevents diastolic dysfunction development, but lacks hepatoprotective effect in an aged mouse model of NASH JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 13 PY - 2023 IS - 1 PG - 14 SN - 2045-2322 DO - 10.1038/s41598-022-26896-3 UR - https://m2.mtmt.hu/api/publication/33547688 ID - 33547688 AB - Interleukin-1β (IL-1β) is a key mediator of non-alcoholic steatohepatitis (NASH), a chronic liver disease, and of systemic inflammation-driven aging. IL-1β contributes to cardio-metabolic decline, and may promote hepatic oncogenic transformation. Therefore, IL-1β is a potential therapeutic target in these pathologies. We aimed to investigate the hepatic and cardiac effects of an IL-1β targeting monoclonal antibody in an aged mouse model of NASH. 24 months old male C57Bl/6J mice were fed with control or choline deficient (CDAA) diet and were treated with isotype control or anti-IL-1β Mab for 8 weeks. Cardiac functions were assessed by conventional—and 2D speckle tracking echocardiography. Liver samples were analyzed by immunohistochemistry and qRT-PCR. Echocardiography revealed improved cardiac diastolic function in anti-IL-1β treated mice with NASH. Marked hepatic fibrosis developed in CDAA-fed group, but IL-1β inhibition affected fibrosis only at transcriptomic level. Hepatic inflammation was not affected by the IL-1β inhibitor. PCNA staining revealed intensive hepatocyte proliferation in CDAA-fed animals, which was not influenced by neutralization of IL-1β. IL-1β inhibition increased hepatic expression of Pd-1 and Ctla4 , while Pd-l1 expression increased in NASH. In conclusion, IL-1β inhibition improved cardiac diastolic function, but did not ameliorate features of NASH; moreover, even promoted hepatic immune checkpoint expression, with concomitant NASH-related hepatocellular proliferation. LA - English DB - MTMT ER - TY - JOUR AU - Sayour, Viktor Nabil AU - Tóth, Viktória AU - Nagy, Regina Norma AU - Vörös, Imre AU - Gergely, Tamás G AU - Onódi, Zsófia AU - Nagy, Noémi AU - Bödör, Csaba AU - Váradi, Barnabás AU - Ruppert, Mihály AU - Radovits, Tamás AU - Bleckwedel, Federico AU - Zelarayán, Laura C. AU - Pacher, Pál AU - Ágg, Bence AU - Görbe, Anikó AU - Ferdinandy, Péter AU - Varga, Zoltán TI - Droplet Digital PCR Is a Novel Screening Method Identifying Potential Cardiac G-Protein-Coupled Receptors as Candidate Pharmacological Targets in a Rat Model of Pressure-Overload-Induced Cardiac Dysfunction JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 18 PG - 18 SN - 1661-6596 DO - 10.3390/ijms241813826 UR - https://m2.mtmt.hu/api/publication/34136194 ID - 34136194 N1 - Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, 1085, Hungary HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, 1085, Hungary MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, 1085, Hungary 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, 1085, Hungary Heart and Vascular Center, Semmelweis University, Budapest, 1085, Hungary Institute of Pharmacology and Toxicology, University Medical Center Goettingen (UMG), Göttingen, 37075, Germany German Center for Cardiovascular Research (DZHK) Partner Site, Goettingen, 37075, Germany Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Rockville, 20852, MD, United States MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, 1085, Hungary Pharmahungary Group, Szeged, 6720, Hungary Export Date: 21 May 2025; Cited By: 8; Correspondence Address: Z.V. Varga; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, 1085, Hungary; email: varga.zoltan@med.semmelweis-univ.hu AB - The identification of novel drug targets is needed to improve the outcomes of heart failure (HF). G-protein-coupled receptors (GPCRs) represent the largest family of targets for already approved drugs, thus providing an opportunity for drug repurposing. Here, we aimed (i) to investigate the differential expressions of 288 cardiac GPCRs via droplet digital PCR (ddPCR) and bulk RNA sequencing (RNAseq) in a rat model of left ventricular pressure-overload; (ii) to compare RNAseq findings with those of ddPCR; and (iii) to screen and test for novel, translatable GPCR drug targets in HF. Male Wistar rats subjected to transverse aortic constriction (TAC, n = 5) showed significant systolic dysfunction vs. sham operated animals (SHAM, n = 5) via echocardiography. In TAC vs. SHAM hearts, RNAseq identified 69, and ddPCR identified 27 significantly differentially expressed GPCR mRNAs, 8 of which were identified using both methods, thus showing a correlation between the two methods. Of these, Prostaglandin-F2α-receptor (Ptgfr) was further investigated and localized on cardiomyocytes and fibroblasts in murine hearts via RNA-Scope. Antagonizing Ptgfr via AL-8810 reverted angiotensin-II-induced cardiomyocyte hypertrophy in vitro. In conclusion, using ddPCR as a novel screening method, we were able to identify GPCR targets in HF. We also show that the antagonism of Ptgfr could be a novel target in HF by alleviating cardiomyocyte hypertrophy. LA - English DB - MTMT ER - TY - JOUR AU - Batkai, Sandor AU - Genschel, Celina AU - Viereck, Janika AU - Rump, Steffen AU - Bär, Christian AU - Borchert, Tobias AU - Traxler, Denise AU - Riesenhuber, Martin AU - Spannbauer, Andreas AU - Lukovic, Dominika AU - Zlabinger, Katrin AU - Hašimbegović, Ena AU - Winkler, Johannes AU - Garamvölgyi, Rita AU - Neitzel, Sonja AU - Gyöngyösi, Mariann AU - Thum, Thomas TI - CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure JF - EUROPEAN HEART JOURNAL J2 - EUR HEART J VL - 42 PY - 2021 IS - 2 SP - 192 EP - 201 PG - 10 SN - 0195-668X DO - 10.1093/eurheartj/ehaa791 UR - https://m2.mtmt.hu/api/publication/31643621 ID - 31643621 N1 - Funding Agency and Grant Number: Cardior Pharmaceuticals GmbH Funding text: The study was supported by Cardior Pharmaceuticals GmbH. AB - Cardiac miR-132 activation leads to adverse remodelling and pathological hypertrophy. CDR132L is a synthetic lead-optimized oligonucleotide inhibitor with proven preclinical efficacy and safety in heart failure (HF) early after myocardial infarction (MI), and recently completed clinical evaluation in a Phase 1b study (NCT04045405). The aim of the current study was to assess safety and efficacy of CDR132L in a clinically relevant large animal (pig) model of chronic heart failure following MI.In a chronic model of post-MI HF, slow-growing pigs underwent 90 min left anterior descending artery occlusion followed by reperfusion. Animals were randomized and treatment started 1-month post-MI. Monthly intravenous (IV) treatments of CDR132L over 3 or 5 months (3× or 5×) were applied in a blinded randomized placebo-controlled fashion. Efficacy was evaluated based on serial magnetic resonance imaging, haemodynamic, and biomarker analyses. The treatment regime provided sufficient tissue exposure and CDR132L was well tolerated. Overall, CDR132L treatment significantly improved cardiac function and reversed cardiac remodelling. In addition to the systolic recovery, diastolic function was also ameliorated in this chronic model of HF.Monthly repeated dosing of CDR132L is safe and adequate to provide clinically relevant exposure and therapeutic efficacy in a model of chronic post-MI HF. CDR132L thus should be explored as treatment for the broad area of chronic heart failure. LA - English DB - MTMT ER - TY - JOUR AU - Brenner, Gábor AU - Giricz, Zoltán AU - Garamvölgyi, Rita AU - Makkos, András AU - Onódi, Zsófia AU - Sayour, Viktor Nabil AU - Gergely, Tamás G AU - Baranyai, Tamás AU - Petneházy, Örs AU - Kőrösi, Dénes AU - Szabó, P. Gergő AU - Vágó, Hajnalka AU - Dohy, Zsófia AU - Czimbalmos, Csilla AU - Merkely, Béla Péter AU - Boldin-Adamsky, Swetlana AU - Feinstein, Elena AU - Horváth, Iván AU - Ferdinandy, Péter TI - Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs JF - JOVE-JOURNAL OF VISUALIZED EXPERIMENTS J2 - JOVE-J VIS EXP VL - 2021 PY - 2021 IS - 170 PG - 25 SN - 1940-087X DO - 10.3791/61901 UR - https://m2.mtmt.hu/api/publication/31992276 ID - 31992276 N1 - * Megosztott szerzőség LA - English DB - MTMT ER - TY - JOUR AU - Zacchigna, Serena AU - Paldino, Alessia AU - Falcao-Pires, Ines AU - Daskalopoulos, Evangelos P. AU - Dal, Ferro Matteo AU - Vodret, Simone AU - Lesizza, Pierluigi AU - Cannata, Antonio AU - Miranda-Silva, Daniela AU - Lourenco, Andre P. AU - Pinamonti, Bruno AU - Sinagra, Gianfranco AU - Weinberger, Florian AU - Eschenhagen, Thomas AU - Carrier, Lucie AU - Kehat, Izhak AU - Tocchetti, Carlo G. AU - Russo, Michele AU - Ghigo, Alessandra AU - Cimino, James AU - Hirsch, Emilio AU - Dawson, Dana AU - Ciccarelli, Michele AU - Oliveti, Marco AU - Linke, Wolfgang A. AU - Cuijpers, Ilona AU - Heymans, Stephane AU - Hamdani, Nazha AU - de, Boer Martine AU - Duncker, Dirk J. AU - Kuster, Diederik AU - van, der Velden Jolanda AU - Beauloye, Christophe AU - Bertrand, Luc AU - Mayr, Manuel AU - Giacca, Mauro AU - Leuschner, Florian AU - Backs, Johannes AU - Thum, Thomas TI - Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents: a position paper of the ESC Working Group on Myocardial Function JF - CARDIOVASCULAR RESEARCH J2 - CARDIOVASC RES VL - 117 PY - 2021 IS - 1 SP - 43 EP - 59 PG - 17 SN - 0008-6363 DO - 10.1093/cvr/cvaa110 UR - https://m2.mtmt.hu/api/publication/32277097 ID - 32277097 AB - Echocardiography is a reliable and reproducible method to assess non-invasively cardiac function in clinical and experimental research. Significant progress in the development of echocardiographic equipment and transducers has led to the successful translation of this methodology from humans to rodents, allowing for the scoring of disease severity and progression, testing of new drugs, and monitoring cardiac function in genetically modified or pharmacologically treated animals. However, as yet, there is no standardization in the procedure to acquire echocardiographic measurements in small animals. This position paper focuses on the appropriate acquisition and analysis of echocardiographic parameters in adult mice and rats, and provides reference values, representative images, and videos for the accurate and reproducible quantification of left ventricular function in healthy and pathological conditions. [GRAPHICS] . LA - English DB - MTMT ER - TY - JOUR AU - Foinquinos, Ariana AU - Batkai, Sandor AU - Genschel, Celina AU - Viereck, Janika AU - Rump, Steffen AU - Gyöngyösi, Mariann AU - Traxler, Denise AU - Riesenhuber, Martin AU - Spannbauer, Andreas AU - Lukovic, Dominika AU - Weber, Natalie AU - Zlabinger, Katrin AU - Hašimbegović, Ena AU - Winkler, Johannes AU - Fiedler, Jan AU - Dangwal, Seema AU - Fischer, Martin AU - Roche, Jeanne de la AU - Wojciechowski, Daniel AU - Kraft, Theresia AU - Garamvölgyi, Rita AU - Neitzel, Sonja AU - Chatterjee, Shambhabi AU - Yin, Xiaoke AU - Bär, Christian AU - Mayr, Manuel AU - Xiao, Ke AU - Thum, Thomas TI - Preclinical development of a miR-132 inhibitor for heart failure treatment JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 11 PY - 2020 IS - 1 PG - 10 SN - 2041-1723 DO - 10.1038/s41467-020-14349-2 UR - https://m2.mtmt.hu/api/publication/31158972 ID - 31158972 LA - English DB - MTMT ER -