GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    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
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 18 ( 2023-09-07), p. 13826-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 18 ( 2023-09-07), p. 13826-
    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, 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.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms241813826
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    IL-1β neutralization prevents diastolic dysfunction development, but lacks hepatoprotective effect in an aged mouse model of NASH
    Springer Science and Business Media LLC ; 2023
    In:  Scientific Reports Vol. 13, No. 1 ( 2023-01-07)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2023-01-07)
    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.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-022-26896-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2615211-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Characterization of immune checkpoint inhibitor‐induced cardiotoxicity reveals interleukin‐17A as a driver of cardiac dysfunction after anti‐PD‐1 treatment
    Wiley ; 2023
    In:  British Journal of Pharmacology Vol. 180, No. 6 ( 2023-03), p. 740-761
    Details
    In: British Journal of Pharmacology, Wiley, Vol. 180, No. 6 ( 2023-03), p. 740-761
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0007-1188 , 1476-5381
    URL: Issue
    URL: Article
    DOI: 10.1111/bph.v180.6
    DOI: 10.1111/bph.15984
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2029728-2
    SSG: 15,3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Hidden Cardiotoxicity of Rofecoxib Can be Revealed in Experimental Models of Ischemia/Reperfusion
    MDPI AG ; 2020
    In:  Cells Vol. 9, No. 3 ( 2020-02-26), p. 551-
    Details
    In: Cells, MDPI AG, Vol. 9, No. 3 ( 2020-02-26), p. 551-
    Abstract: Cardiac adverse effects are among the leading causes of the discontinuation of clinical trials and the withdrawal of drugs from the market. The novel concept of ‘hidden cardiotoxicity’ is defined as cardiotoxicity of a drug that manifests in the diseased (e.g., ischemic/reperfused), but not in the healthy heart or as a drug-induced deterioration of cardiac stress adaptation (e.g., ischemic conditioning). Here, we aimed to test if the cardiotoxicity of a selective COX-2 inhibitor rofecoxib that was revealed during its clinical use, i.e., increased occurrence of proarrhythmic and thrombotic events, could have been revealed in early phases of drug development by using preclinical models of ischemia/reperfusion (I/R) injury. Rats that were treated with rofecoxib or vehicle for four weeks were subjected to 30 min. coronary artery occlusion and 120 min. reperfusion with or without cardioprotection that is induced by ischemic preconditioning (IPC). Rofecoxib increased overall the arrhythmias including ventricular fibrillation (VF) during I/R. The proarrhythmic effect of rofecoxib during I/R was not observed in the IPC group. Rofecoxib prolonged the action potential duration (APD) in isolated papillary muscles, which was not seen in the simulated IPC group. Interestingly, while showing hidden cardiotoxicity manifested as a proarrhythmic effect during I/R, rofecoxib decreased the infarct size and increased the survival of adult rat cardiac myocytes that were subjected to simulated I/R injury. This is the first demonstration that rofecoxib increased acute mortality due to its proarrhythmic effect via increased APD during I/R. Rofecoxib did not interfere with the cardiprotective effect of IPC; moreover, IPC was able to protect against rofecoxib-induced hidden cardiotoxicity. These results show that cardiac safety testing with simple preclinical models of I/R injury uncovers hidden cardiotoxicity of rofecoxib and might reveal the hidden cardiotoxicity of other drugs.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells9030551
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2661518-6
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Effects of Bempedoic Acid in Acute Myocardial Infarction in Rats: No Cardioprotection and No Hidden Cardiotoxicity
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 2 ( 2023-01-13), p. 1585-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 2 ( 2023-01-13), p. 1585-
    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.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24021585
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo
    MDPI AG ; 2022
    In:  Pharmaceuticals Vol. 15, No. 9 ( 2022-08-26), p. 1055-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 15, No. 9 ( 2022-08-26), p. 1055-
    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.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph15091055
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2193542-7
    SSG: 15,3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...