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Article ; Online: Immune checkpoints in cardiac physiology and pathology: therapeutic targets for heart failure.

Gergely, Tamás G / Drobni, Zsófia D / Kallikourdis, Marinos / Zhu, Han / Meijers, Wouter C / Neilan, Tomas G / Rassaf, Tienush / Ferdinandy, Péter / Varga, Zoltán V

Nature reviews. Cardiology

2024

Abstract: Immune checkpoint molecules are physiological regulators of the adaptive immune response. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies targeting programmed cell death protein 1 or cytotoxic T lymphocyte-associated protein 4, have ... ...

Abstract	Immune checkpoint molecules are physiological regulators of the adaptive immune response. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies targeting programmed cell death protein 1 or cytotoxic T lymphocyte-associated protein 4, have revolutionized cancer treatment and their clinical use is increasing. However, ICIs can cause various immune-related adverse events, including acute and chronic cardiotoxicity. Of these cardiovascular complications, ICI-induced acute fulminant myocarditis is the most studied, although emerging clinical and preclinical data are uncovering the importance of other ICI-related chronic cardiovascular complications, such as accelerated atherosclerosis and non-myocarditis-related heart failure. These complications could be more difficult to diagnose, given that they might only be present alongside other comorbidities. The occurrence of these complications suggests a potential role of immune checkpoint molecules in maintaining cardiovascular homeostasis, and disruption of physiological immune checkpoint signalling might thus lead to cardiac pathologies, including heart failure. Although inflammation is a long-known contributor to the development of heart failure, the therapeutic targeting of pro-inflammatory pathways has not been successful thus far. The increasingly recognized role of immune checkpoint molecules in the failing heart highlights their potential use as immunotherapeutic targets for heart failure. In this Review, we summarize the available data on ICI-induced cardiac dysfunction and heart failure, and discuss how immune checkpoint signalling is altered in the failing heart. Furthermore, we describe how pharmacological targeting of immune checkpoints could be used to treat heart failure.
Language	English
Publishing date	2024-01-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2490375-9
ISSN	1759-5010 ; 1759-5002
ISSN (online)	1759-5010
ISSN	1759-5002
DOI	10.1038/s41569-023-00986-9
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Article ; Online: Effects of Bempedoic Acid in Acute Myocardial Infarction in Rats: No Cardioprotection and No Hidden Cardiotoxicity.

Gergely, Tamás G / Brenner, Gábor B / Nagy, Regina N / Sayour, Nabil V / Makkos, András / Kovácsházi, Csenger / Tian, Huimin / Schulz, Rainer / Giricz, Zoltán / Görbe, Anikó / Ferdinandy, Péter

International journal of molecular sciences

2023 Volume 24, Issue 2

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Rats ; Arrhythmias, Cardiac/drug therapy ; Arrhythmias, Cardiac/etiology ; Arrhythmias, Cardiac/prevention & control ; Cardiotoxicity ; Ischemic Preconditioning, Myocardial ; Lipids/therapeutic use ; Myocardial Infarction/drug therapy ; Myocardial Infarction/prevention & control ; Myocardial Ischemia ; Myocardial Reperfusion Injury/prevention & control ; Rats, Wistar
Chemical Substances	8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (1EJ6Z6Q368) ; Lipids
Language	English
Publishing date	2023-01-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24021585
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Article ; Online: IL-1β neutralization prevents diastolic dysfunction development, but lacks hepatoprotective effect in an aged mouse model of NASH.

Kucsera, Dániel / Tóth, Viktória E / Sayour, Nabil V / Kovács, Tamás / Gergely, Tamás G / Ruppert, Mihály / Radovits, Tamás / Fábián, Alexandra / Kovács, Attila / Merkely, Béla / Ferdinandy, Péter / Varga, Zoltán V

Scientific reports

2023 Volume 13, Issue 1, Page(s) 356

Abstract: 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. ... ...

Abstract	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.
MeSH term(s)	Male ; Mice ; Animals ; Non-alcoholic Fatty Liver Disease/pathology ; Interleukin-1beta/metabolism ; Liver/metabolism ; Liver Cirrhosis/pathology ; Disease Models, Animal ; Fibrosis ; Mice, Inbred C57BL
Chemical Substances	Interleukin-1beta ; CDAA (93-71-0)
Language	English
Publishing date	2023-01-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-26896-3
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Article ; Online: 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.

Sayour, Nabil V / Tóth, Viktória É / Nagy, Regina N / Vörös, Imre / Gergely, Tamás G / Onódi, Zsófia / Nagy, Noémi / Bödör, Csaba / Váradi, Barnabás / Ruppert, Mihály / Radovits, Tamás / Bleckwedel, Federico / Zelarayán, Laura C / Pacher, Pal / Ágg, Bence / Görbe, Anikó / Ferdinandy, Péter / Varga, Zoltán V

International journal of molecular sciences

2023 Volume 24, Issue 18

Abstract: 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. ... ...

Abstract	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,
MeSH term(s)	Male ; Rats ; Mice ; Animals ; Rats, Wistar ; Heart Failure/genetics ; Myocytes, Cardiac ; Polymerase Chain Reaction ; Hypertrophy
Language	English
Publishing date	2023-09-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241813826
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Article ; Online: Cardioprotective efficacy of limb remote ischaemic preconditioning in rats: discrepancy between a meta-analysis and a three-centre in vivo study.

Sayour, Nabil V / Brenner, Gábor B / Makkos, András / Kiss, Bernadett / Kovácsházi, Csenger / Gergely, Tamás G / Aukrust, Sverre Groever / Tian, Huimin / Zenkl, Viktória / Gömöri, Kamilla / Szabados, Tamara / Bencsik, Péter / Heinen, Andre / Schulz, Rainer / Baxter, Gary F / Zuurbier, Coert J / Vokó, Zoltán / Ferdinandy, Péter / Giricz, Zoltán

Cardiovascular research

2023 Volume 119, Issue 6, Page(s) 1336–1351

Abstract: Aims: Remote ischaemic preconditioning (RIPC) is a robust cardioprotective intervention in preclinical studies. To establish a working and efficacious RIPC protocol in our laboratories, we performed randomized, blinded in vivo studies in three study ... ...

Abstract	Aims: Remote ischaemic preconditioning (RIPC) is a robust cardioprotective intervention in preclinical studies. To establish a working and efficacious RIPC protocol in our laboratories, we performed randomized, blinded in vivo studies in three study centres in rats, with various RIPC protocols. To verify that our experimental settings are in good alignment with in vivo rat studies showing cardioprotection by limb RIPC, we performed a systematic review and meta-analysis. In addition, we investigated the importance of different study parameters. Methods and results: Male Wistar rats were subjected to 20-45 min cardiac ischaemia followed by 120 min reperfusion with or without preceding RIPC by 3 or 4 × 5-5 min occlusion/reperfusion of one or two femoral vessels by clamping, tourniquet, or pressure cuff. RIPC did not reduce infarct size (IS), microvascular obstruction, or arrhythmias at any study centres. Systematic review and meta-analysis focusing on in vivo rat models of myocardial ischaemia/reperfusion injury with limb RIPC showed that RIPC reduces IS by 21.28% on average. In addition, the systematic review showed methodological heterogeneity and insufficient reporting of study parameters in a high proportion of studies. Conclusion: We report for the first time the lack of cardioprotection by RIPC in rats, assessed in individually randomized, blinded in vivo studies, involving three study centres, using different RIPC protocols. These results are in discrepancy with the meta-analysis of similar in vivo rat studies; however, no specific methodological reason could be identified by the systematic review, probably due to the overall insufficient reporting of several study parameters that did not improve over the past two decades. These results urge for publication of more well-designed and well-reported studies, irrespective of the outcome, which are required for preclinical reproducibility, and the development of clinically translatable cardioprotective interventions.
MeSH term(s)	Rats ; Male ; Animals ; Rats, Wistar ; Reproducibility of Results ; Ischemic Preconditioning/methods ; Myocardial Reperfusion Injury/prevention & control
Language	English
Publishing date	2023-01-30
Publishing country	England
Document type	Systematic Review ; Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvad024
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Article: Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo.

Weber, Bennet Y / Brenner, Gábor B / Kiss, Bernadett / Gergely, Tamás G / Sayour, Nabil V / Tian, Huimin / Makkos, András / Görbe, Anikó / Ferdinandy, Péter / Giricz, Zoltán

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 9

Abstract: Clinical observations are highly inconsistent with the use of the antidiabetic rosiglitazone regarding its associated increased risk of myocardial infarction. This may be due to its hidden cardiotoxic properties that have only become evident during post- ... ...

Abstract	Clinical observations are highly inconsistent with the use of the antidiabetic rosiglitazone regarding its associated increased risk of myocardial infarction. This may be due to its hidden cardiotoxic properties that have only become evident during post-marketing studies. Therefore, we aimed to investigate the hidden cardiotoxicity of rosiglitazone in ischemia/reperfusion (I/R) injury models. Rats were treated orally with either 0.8 mg/kg/day rosiglitazone or vehicle for 28 days and subjected to I/R with or without cardioprotective ischemic preconditioning (IPC). Rosiglitazone did not affect mortality, arrhythmia score, or infarct size during I/R. However, rosiglitazone abolished the antiarrhythmic effects of IPC. To investigate the direct effect of rosiglitazone on cardiomyocytes, we utilized adult rat cardiomyocytes (ARCMs), AC16, and differentiated AC16 (diffAC16) human cardiac cell lines. These were subjected to simulated I/R in the presence of rosiglitazone. Rosiglitazone improved cell survival of ARCMs at 0.3 μM. At 0.1 and 0.3 μM, rosiglitazone improved cell survival of AC16s but not that of diffAC16s. This is the first demonstration that chronic administration of rosiglitazone does not result in major hidden cardiotoxic effects in myocardial I/R injury models. However, the inhibition of the antiarrhythmic effects of IPC may have some clinical relevance that needs to be further explored.
Language	English
Publishing date	2022-08-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15091055
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Article: Saxagliptin Cardiotoxicity in Chronic Heart Failure: The Role of DPP4 in the Regulation of Neuropeptide Tone.

Vörös, Imre / Onódi, Zsófia / Tóth, Viktória Éva / Gergely, Tamás G / Sághy, Éva / Görbe, Anikó / Kemény, Ágnes / Leszek, Przemyslaw / Helyes, Zsuzsanna / Ferdinandy, Péter / Varga, Zoltán V

Biomedicines

2022 Volume 10, Issue 7

Abstract: Dipeptidyl-peptidase-4 (DPP4) inhibitors are novel medicines for diabetes. The SAVOR-TIMI-53 clinical trial revealed increased heart-failure-associated hospitalization in saxagliptin-treated patients. Although this side effect could limit therapeutic use, ...

Abstract	Dipeptidyl-peptidase-4 (DPP4) inhibitors are novel medicines for diabetes. The SAVOR-TIMI-53 clinical trial revealed increased heart-failure-associated hospitalization in saxagliptin-treated patients. Although this side effect could limit therapeutic use, the mechanism of this potential cardiotoxicity is unclear. We aimed to establish a cellular platform to investigate DPP4 inhibition and the role of its neuropeptide substrates substance P (SP) and neuropeptide Y (NPY), and to determine the expression of DDP4 and its neuropeptide substrates in the human heart. Western blot, radio-, enzyme-linked immuno-, and RNA scope assays were performed to investigate the expression of DPP4 and its substrates in human hearts. Calcein-based viability measurements and scratch assays were used to test the potential toxicity of DPP4 inhibitors. Cardiac expression of DPP4 and NPY decreased in heart failure patients. In human hearts, DPP4 mRNA is detectable mainly in cardiomyocytes and endothelium. Treatment with DPP4 inhibitors alone/in combination with neuropeptides did not affect viability but in scratch assays neuropeptides decreased, while saxagliptin co-administration increased fibroblast migration in isolated neonatal rat cardiomyocyte-fibroblast co-culture. Decreased DPP4 activity takes part in the pathophysiology of end-stage heart failure. DPP4 compensates against the elevated sympathetic activity and altered neuropeptide tone. Its inhibition decreases this adaptive mechanism, thereby exacerbating myocardial damage.
Language	English
Publishing date	2022-07-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10071573
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Article ; Online: Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs.

Brenner, Gábor B / Giricz, Zoltán / Garamvölgyi, Rita / Makkos, András / Onódi, Zsófia / Sayour, Nabil V / Gergely, Tamás G / Baranyai, Tamás / Petneházy, Örs / Kőrösi, Dénes / Szabó, Gergő P / Vago, Hajnalka / Dohy, Zsófia / Czimbalmos, Csilla / Merkely, Béla / Boldin-Adamsky, Swetlana / Feinstein, Elena / Horváth, Iván G / Ferdinandy, Péter

Journal of visualized experiments : JoVE

2021 , Issue 170

Abstract: The development of heart failure is the most powerful predictor of long-term mortality in patients surviving acute myocardial infarction (MI). There is an unmet clinical need for prevention and therapy of post-myocardial infarction heart failure (post-MI ...

Abstract	The development of heart failure is the most powerful predictor of long-term mortality in patients surviving acute myocardial infarction (MI). There is an unmet clinical need for prevention and therapy of post-myocardial infarction heart failure (post-MI HF). Clinically relevant pig models of post-MI HF are prerequisites for final proof-of-concept studies before entering into clinical trials in drug and medical device development. Here we aimed to characterize a closed-chest porcine model of post-MI HF in adult Göttingen minipigs with long-term follow-up including serial cardiac magnetic resonance imaging (CMRI) and to compare it with the commonly used Landrace pig model. MI was induced by intraluminal balloon occlusion of the left anterior descending coronary artery for 120 min in Göttingen minipigs and for 90 min in Landrace pigs, followed by reperfusion. CMRI was performed to assess cardiac morphology and function at baseline in both breeds and at 3 and 6 months in Göttingen minipigs and at 2 months in Landrace pigs, respectively. Scar sizes were comparable in the two breeds, but MI resulted in a significant decrease of left ventricular ejection fraction (LVEF) only in Göttingen minipigs, while Landrace pigs did not show a reduction of LVEF. Right ventricular (RV) ejection fraction increased in both breeds despite the negligible RV scar sizes. In contrast to the significant increase of left ventricular end-diastolic (LVED) mass in Landrace pigs at 2 months, Göttingen minipigs showed a slight increase in LVED mass only at 6 months. In summary, this is the first characterization of post-MI HF in Göttingen minipigs in comparison to Landrace pigs, showing that the Göttingen minipig model reflects post-MI HF parameters comparable to the human pathology. We conclude that the Göttingen minipig model is superior to the Landrace pig model to study the development of post-MI HF.
MeSH term(s)	Animals ; Coronary Occlusion/diagnostic imaging ; Coronary Occlusion/physiopathology ; Disease Models, Animal ; Female ; Heart/diagnostic imaging ; Heart/physiopathology ; Heart Failure/diagnostic imaging ; Heart Failure/etiology ; Heart Failure/physiopathology ; Magnetic Resonance Imaging ; Myocardial Infarction/complications ; Myocardial Infarction/diagnostic imaging ; Myocardial Infarction/physiopathology ; Myocardial Reperfusion ; Myocardial Reperfusion Injury/physiopathology ; Swine ; Swine, Miniature ; Ventricular Function, Left
Language	English
Publishing date	2021-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/61901
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Article ; Online: Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment.

Gergely, Tamás G / Kucsera, Dániel / Tóth, Viktória E / Kovács, Tamás / Sayour, Nabil V / Drobni, Zsófia D / Ruppert, Mihály / Petrovich, Balázs / Ágg, Bence / Onódi, Zsófia / Fekete, Nóra / Pállinger, Éva / Buzás, Edit I / Yousif, Laura I / Meijers, Wouter C / Radovits, Tamás / Merkely, Béla / Ferdinandy, Péter / Varga, Zoltán V

British journal of pharmacology

2022 Volume 180, Issue 6, Page(s) 740–761

Abstract: Background and purpose: Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause ... ...

Abstract	Background and purpose: Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI-induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD-1 inhibition on cardiac function and explore the molecular mechanisms of ICI-induced cardiotoxicity. Experimental approach: C57BL6/J and BALB/c mice were treated with isotype control or anti-PD-1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT-PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow-up experiments, anti-CD4 and anti-IL-17A antibodies were used along with PD-1 blockade in C57BL/6J mice. Key results: Anti-PD-1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD-1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL-17A prevented anti-PD-1-induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation. Conclusions: PD-1 blockade induces cardiac dysfunction in mice with increased IL-17 signalling in the thymus. Pharmacological inhibition of IL-17A treatment prevents ICI-induced cardiac dysfunction.
MeSH term(s)	Mice ; Animals ; Cardiotoxicity/etiology ; Immune Checkpoint Inhibitors/adverse effects ; Interleukin-17 ; Mice, Inbred C57BL ; Heart Diseases ; Inflammation/complications
Chemical Substances	Immune Checkpoint Inhibitors ; Interleukin-17
Language	English
Publishing date	2022-12-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.15984
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Article ; Online: Systematic transcriptomic and phenotypic characterization of human and murine cardiac myocyte cell lines and primary cardiomyocytes reveals serious limitations and low resemblances to adult cardiac phenotype.

Onódi, Zsófia / Visnovitz, Tamás / Kiss, Bernadett / Hambalkó, Szabolcs / Koncz, Anna / Ágg, Bence / Váradi, Barnabás / Tóth, Viktória É / Nagy, Regina N / Gergely, Tamás G / Gergő, Dorottya / Makkos, András / Pelyhe, Csilla / Varga, Nóra / Reé, Dóra / Apáti, Ágota / Leszek, Przemyslaw / Kovács, Tamás / Nagy, Nándor /

Ferdinandy, Péter / Buzás, Edit I / Görbe, Anikó / Giricz, Zoltán / Varga, Zoltán V

Journal of molecular and cellular cardiology

2021 Volume 165, Page(s) 19–30

Abstract: Background: Cardiac cell lines and primary cells are widely used in cardiovascular research. Despite increasing number of publications using these models, comparative characterization of these cell lines has not been performed, therefore, their ... ...

Abstract	Background: Cardiac cell lines and primary cells are widely used in cardiovascular research. Despite increasing number of publications using these models, comparative characterization of these cell lines has not been performed, therefore, their limitations are undetermined. We aimed to compare cardiac cell lines to primary cardiomyocytes and to mature cardiac tissues in a systematic manner. Methods and results: Cardiac cell lines (H9C2, AC16, HL-1) were differentiated with widely used protocols. Left ventricular tissue, neonatal primary cardiomyocytes, and human induced pluripotent stem cell-derived cardiomyocytes served as reference tissue or cells. RNA expression of cardiac markers (e.g. Tnnt2, Ryr2) was markedly lower in cell lines compared to references. Differentiation induced increase in cardiac- and decrease in embryonic markers however, the overall transcriptomic profile and annotation to relevant biological processes showed consistently less pronounced cardiac phenotype in all cell lines in comparison to the corresponding references. Immunocytochemistry confirmed low expressions of structural protein sarcomeric alpha-actinin, troponin I and caveolin-3 in cell lines. Susceptibility of cell lines to sI/R injury in terms of viability as well as mitochondrial polarization differed from the primary cells irrespective of their degree of differentiation. Conclusion: Expression patterns of cardiomyocyte markers and whole transcriptomic profile, as well as response to sI/R, and to hypertrophic stimuli indicate low-to-moderate similarity of cell lines to primary cells/cardiac tissues regardless their differentiation. Low resemblance of cell lines to mature adult cardiac tissue limits their potential use. Low translational value should be taken into account while choosing a particular cell line to model cardiomyocytes.
MeSH term(s)	Animals ; Biomarkers/metabolism ; Cell Differentiation/genetics ; Cell Line ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Mice ; Myocytes, Cardiac/metabolism ; Phenotype ; Transcriptome
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-12-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2021.12.007
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