Basic Research in Cardiology最新文献

Inter-organ communication: pathways and targets to cardioprotection and neuro-protection. A report from the 12th Hatter Cardiovascular Institute workshop 器官间交流：心脏保护和神经保护的途径与目标。第 12 届哈特心血管研究所研讨会报告

IF 9.5 1区医学

Basic Research in Cardiology Pub Date : 2024-12-16 DOI: 10.1007/s00395-024-01094-6

L. Pearce, C. Galán-Arriola, R. M. Bell, R. D. Carr, J. Cunningham, S. M. Davidson, A. K. Ghosh, S. Giesz, P. Golforoush, A. V. Gourine, D. M. Hermann, G. Heusch, B. Ibanez, S. Beikoghli Kalkhoran, S. Lecour, K. Lukhna, M. Ntsekhe, M. N. Sack, R. J. Unwin, G. Vilahur, J. M. Walker, D. M. Yellon

{"title":"Inter-organ communication: pathways and targets to cardioprotection and neuro-protection. A report from the 12th Hatter Cardiovascular Institute workshop","authors":"L. Pearce, C. Galán-Arriola, R. M. Bell, R. D. Carr, J. Cunningham, S. M. Davidson, A. K. Ghosh, S. Giesz, P. Golforoush, A. V. Gourine, D. M. Hermann, G. Heusch, B. Ibanez, S. Beikoghli Kalkhoran, S. Lecour, K. Lukhna, M. Ntsekhe, M. N. Sack, R. J. Unwin, G. Vilahur, J. M. Walker, D. M. Yellon","doi":"10.1007/s00395-024-01094-6","DOIUrl":"https://doi.org/10.1007/s00395-024-01094-6","url":null,"abstract":"A long-standing aim in the setting of various pathologies including acute myocardial infarction, chronic kidney disease (CKD), and ischaemic stroke, has been to identify successful approaches to augment cellular and organ protection. Although the continual evolution and refinement of ideas over the past few decades has allowed the field to progress, we are yet to realise successful clinical translation of this concept. The 12th Hatter Cardiovascular Workshop identified a number of important points and key questions for future research relating to cardio- and neuro-protection and interorgan communication. Specific topics that were discussed include the ‘cardio-metabolic-renal’ axis of organ protection, the parasympathetic signalling hypothesis, the role of the coronary microvasculature in myocardial infarction, the RISK pathway of cardioprotection, extracellular vesicles and the way forward, the future for clinical studies of remote ischaemic conditioning, and new experimental models for cardio-oncology investigations.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"30 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Changes in tumor and cardiac metabolism upon immune checkpoint

IF 9.5 1区医学

Basic Research in Cardiology Pub Date : 2024-12-10 DOI: 10.1007/s00395-024-01092-8

Anna-Sophia Leven, Natalie Wagner, Stephan Nienaber, Daniel Messiha, Alpaslan Tasdogan, Selma Ugurel

{"title":"Changes in tumor and cardiac metabolism upon immune checkpoint","authors":"Anna-Sophia Leven, Natalie Wagner, Stephan Nienaber, Daniel Messiha, Alpaslan Tasdogan, Selma Ugurel","doi":"10.1007/s00395-024-01092-8","DOIUrl":"https://doi.org/10.1007/s00395-024-01092-8","url":null,"abstract":"Cardiovascular disease and cancer are the leading causes of death in the Western world. The associated risk factors are increased by smoking, hypertension, diabetes, sedentary lifestyle, aging, unbalanced diet, and alcohol consumption. Therefore, the study of cellular metabolism has become of increasing importance, with current research focusing on the alterations and adjustments of the metabolism of cancer patients. This may also affect the efficacy and tolerability of anti-cancer therapies such as immune-checkpoint inhibition (ICI). This review will focus on metabolic adaptations and their consequences for various cell types, including cancer cells, cardiac myocytes, and immune cells. Focusing on ICI, we illustrate how anti-cancer therapies interact with metabolism. In addition to the desired tumor response, we highlight that ICI can also lead to a variety of side effects that may impact metabolism or vice versa. With regard to the cardiovascular system, ICI-induced cardiotoxicity is increasingly recognized as one of the most life-threatening adverse events with a mortality of up to 50%. As such, significant efforts are being made to assess the specific interactions and associated metabolic changes associated with ICIs to improve both efficacy and management of side effects.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"47 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The cardio-oncologic burden of breast cancer: molecular mechanisms and importance of preclinical models

IF 9.5 1区医学

Basic Research in Cardiology Pub Date : 2024-12-02 DOI: 10.1007/s00395-024-01090-w

J. Brauer, M. Tumani, N. Frey, L. H. Lehmann

{"title":"The cardio-oncologic burden of breast cancer: molecular mechanisms and importance of preclinical models","authors":"J. Brauer, M. Tumani, N. Frey, L. H. Lehmann","doi":"10.1007/s00395-024-01090-w","DOIUrl":"https://doi.org/10.1007/s00395-024-01090-w","url":null,"abstract":"Breast cancer, the most prevalent cancer affecting women worldwide, poses a significant cardio-oncological burden. Despite advancements in novel therapeutic strategies, anthracyclines, HER2 antagonists, and radiation remain the cornerstones of oncological treatment. However, each carries a risk of cardiotoxicity, though the molecular mechanisms underlying these adverse effects differ. Common mechanisms include DNA damage response, increased reactive oxygen species, and mitochondrial dysfunction, which are key areas of ongoing research for potential cardioprotective strategies. Since these mechanisms are also essential for effective tumor cytotoxicity, we explore tumor-specific effects, particularly in hereditary breast cancer linked to BRCA1 and BRCA2 mutations. These genetic variants impair DNA repair mechanisms, increase the risk of tumorigenesis and possibly for cardiotoxicity from treatments such as anthracyclines and HER2 antagonists. Novel therapies, including immune checkpoint inhibitors, are used in the clinic for triple-negative breast cancer and improve the oncological outcomes of breast cancer patients. This review discusses the molecular mechanisms underlying BRCA dysfunction and the associated pathological pathways. It gives an overview of preclinical models of breast cancer, such as genetically engineered mouse models, syngeneic murine models, humanized mouse models, and various in vitro and ex vivo systems and models to study cardiovascular side effects of breast cancer therapies. Understanding the underlying mechanism of cardiotoxicity and developing cardioprotective strategies in preclinical models are essential for improving treatment outcomes and reducing long-term cardiovascular risks in breast cancer patients.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"16 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Heart-specific NFAT5 knockout suppresses type I interferon signaling and aggravates coxsackievirus-induced myocarditis. 心脏特异性 NFAT5 基因敲除可抑制 I 型干扰素信号传导并加重柯萨奇病毒诱发的心肌炎。

IF 7.5 1区医学

Basic Research in Cardiology Pub Date : 2024-12-01 Epub Date: 2024-06-05 DOI: 10.1007/s00395-024-01058-w

Guangze Zhao, Huifang M Zhang, Ali Reza Nasseri, Fione Yip, Nikita Telkar, Yankuan T Chen, Sana Aghakeshmiri, Christoph Küper, Wan Lam, Wenli Yang, James Zhao, Honglin Luo, Bruce M McManus, Decheng Yang

{"title":"Heart-specific NFAT5 knockout suppresses type I interferon signaling and aggravates coxsackievirus-induced myocarditis.","authors":"Guangze Zhao, Huifang M Zhang, Ali Reza Nasseri, Fione Yip, Nikita Telkar, Yankuan T Chen, Sana Aghakeshmiri, Christoph Küper, Wan Lam, Wenli Yang, James Zhao, Honglin Luo, Bruce M McManus, Decheng Yang","doi":"10.1007/s00395-024-01058-w","DOIUrl":"10.1007/s00395-024-01058-w","url":null,"abstract":"Nuclear factor of activated T cells 5 (NFAT5) is an osmosensitive transcription factor that is well-studied in renal but rarely explored in cardiac diseases. Although the association of Coxsackievirus B3 (CVB3) with viral myocarditis is well-established, the role of NFAT5 in this disease remains largely unexplored. Previous research has demonstrated that NFAT5 restricts CVB3 replication yet is susceptible to cleavage by CVB3 proteases. Using an inducible cardiac-specific Nfat5-knockout mouse model, we uncovered that NFAT5-deficiency exacerbates cardiac pathology, worsens cardiac function, elevates viral load, and reduces survival rates. RNA-seq analysis of CVB3-infected mouse hearts revealed the significant impact of NFAT5-deficiency on gene pathways associated with cytokine signaling and inflammation. Subsequent in vitro and in vivo investigation validated the disruption of the cytokine signaling pathway in response to CVB3 infection, evidenced by reduced expression of key cytokines such as interferon β1 (IFNβ1), C-X-C motif chemokine ligand 10 (CXCL10), interleukin 6 (IL6), among others. Furthermore, NFAT5-deficiency hindered the formation of stress granules, leading to a reduction of important stress granule components, including plakophilin-2, a pivotal protein within the intercalated disc, thereby impacting cardiomyocyte structure and function. These findings unveil a novel mechanism by which NFAT5 inhibits CVB3 replication and pathogenesis through the promotion of antiviral type I interferon signaling and the formation of cytoplasmic stress granules, collectively identifying NFAT5 as a new cardio protective protein.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"1075-1092"},"PeriodicalIF":7.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proprioceptors of the human pericardium. 人体心包的直觉感受器

IF 7.5 1区医学

Basic Research in Cardiology Pub Date : 2024-12-01 Epub Date: 2024-08-09 DOI: 10.1007/s00395-024-01075-9

Lea M Piermaier, Svenja Caspers, Christina Herold, Michael Wolf-Vollenbröker, Patrick Brzoska, Eric Bechler, Timm J Filler

{"title":"Proprioceptors of the human pericardium.","authors":"Lea M Piermaier, Svenja Caspers, Christina Herold, Michael Wolf-Vollenbröker, Patrick Brzoska, Eric Bechler, Timm J Filler","doi":"10.1007/s00395-024-01075-9","DOIUrl":"10.1007/s00395-024-01075-9","url":null,"abstract":"In the human organism, all functions are regulated and, therefore, require a feedback mechanism. This control involves a perception of the spatial tensile state of cardiac tissues. The presence and distribution of respective proprioceptive corpuscles have not been considered so far. Therefore, a comprehensive study of the entire human fibrous pericardium was conducted to describe the presence of proprioceptors, their density, and distribution patterns. Eight human pericardial specimens gained from our body donation program were used to create a three-dimensional map of proprioceptors in the pericardium based on their histological and immunohistochemical identification. The 3D map was generated as a volume-rendered 3D model based on magnetic resonance imaging of the pericardium, to which all identified receptors were mapped. To discover a systematic pattern in receptor distribution, statistical cluster analysis was conducted using the Scikit-learn library in Python. Ruffini-like corpuscles (RLCs) were found in all pericardia and assigned to three histological receptor localizations depending on the fibrous pericardium's layering, with no other corpuscular proprioceptors identified. Cluster analysis revealed that RLCs exhibit a specific topographical arrangement. The highest receptor concentrations occur at the ventricular bulges, where their size reaches its maximum in terms of diameter, and at the perivascular pericardial turn-up. The findings suggest that the pericardium is subject to proprioceptive control. RLCs record lateral shearing between the pericardial sublayers, and their distribution pattern enables the detection of distinct dilatation of the heart. Therefore, the pericardium might have an undiscovered function as a sensor with the RLCs as its anatomical correlate.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"1029-1043"},"PeriodicalIF":7.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia. 在丙酸血症中，肝脏对丙酸的清除能力减弱会增加心脏的氧化应激。

IF 7.5 1区医学

Basic Research in Cardiology Pub Date : 2024-12-01 Epub Date: 2024-07-11 DOI: 10.1007/s00395-024-01066-w

You Wang, Suhong Zhu, Wentao He, Hannah Marchuk, Eva Richard, Lourdes R Desviat, Sarah P Young, Dwight Koeberl, Takhar Kasumov, Xiaoxin Chen, Guo-Fang Zhang

{"title":"The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia.","authors":"You Wang, Suhong Zhu, Wentao He, Hannah Marchuk, Eva Richard, Lourdes R Desviat, Sarah P Young, Dwight Koeberl, Takhar Kasumov, Xiaoxin Chen, Guo-Fang Zhang","doi":"10.1007/s00395-024-01066-w","DOIUrl":"10.1007/s00395-024-01066-w","url":null,"abstract":"Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. Additionally, Pcca-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"1045-1062"},"PeriodicalIF":7.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of ventricular fibrillation on infarct size after myocardial infarction: a translational study 心室颤动对心肌梗死后梗死面积的影响：一项转化研究

IF 9.5 1区医学

Basic Research in Cardiology Pub Date : 2024-11-23 DOI: 10.1007/s00395-024-01091-9

Neven Stevic, Alexandre Pinède, Nathan Mewton, Michel Ovize, Laurent Argaud, Sandrine Lecour, Clément Boiteux, Thomas Bochaton, Martin Cour

{"title":"Effect of ventricular fibrillation on infarct size after myocardial infarction: a translational study","authors":"Neven Stevic, Alexandre Pinède, Nathan Mewton, Michel Ovize, Laurent Argaud, Sandrine Lecour, Clément Boiteux, Thomas Bochaton, Martin Cour","doi":"10.1007/s00395-024-01091-9","DOIUrl":"https://doi.org/10.1007/s00395-024-01091-9","url":null,"abstract":"Ventricular fibrillation (VF)-induced cardiac arrest frequently complicates ST-segment elevation myocardial infarction (STEMI). Although larger infarct sizes (IS) correlate with a higher risk of VF, the influence of VF itself on IS has remained poorly investigated. To address this knowledge gap, we analyzed the effect of VF on IS in patients and two experimental models. From a prospective cohort, 30 STEMI patients with VF were matched 1:2 with STEMI patients without VF on the common determinants of IS. The primary endpoint was IS, assessed using the 48-h area under the curve (AUC) for troponin. We also compared IS in pigs with/without spontaneous VF during STEMI (n = 15/group), and in an isolated rat heart model of myocardial infarction with/without electrically induced VF (n = 7/group). After matching, the patient characteristics, including the area at risk (AR), were similar. IS was 33% lower in the VF group compared to the control group (troponin AUC 1.6 [0.5–3.3] 106 arbitrary units vs. 2.4 [0.9–4.1] 106 arbitrary units; p < 0.05), but infarct scar size (assessed using MRI and ECG) did not differ between the groups at 1 and 6 months. In both experimental models, IS, expressed as a percentage of AR, was lower (p < 0.05) in the VF group than in the control group. When common determinants of IS are comparable, VF occurring prior to myocardial infarction reperfusion appears to be associated with smaller IS. Nevertheless, this finding, observed under specific experimental conditions and in a highly selected group of patients, was not associated with reduced infarct scar size.Registration (HIBISCUS-STEMI cohort): ClinicalTrials.gov NCT05794022.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"20 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

4E-BP3 deficiency impairs dendritic cell activation and CD4+ T cell differentiation and attenuates α-myosin-specific T cell-mediated myocarditis in mice 4E-BP3 缺乏会损害树突状细胞活化和 CD4+ T 细胞分化，并减轻 α 肌球蛋白特异性 T 细胞介导的小鼠心肌炎

IF 9.5 1区医学

Basic Research in Cardiology Pub Date : 2024-11-09 DOI: 10.1007/s00395-024-01089-3

Siqi Li, Kazuko Tajiri, Zixun Yuan, Yoshiko Murakata, Zonghu Song, Seiya Mizuno, Dongzhu Xu, Nobuyuki Murakoshi

{"title":"4E-BP3 deficiency impairs dendritic cell activation and CD4+ T cell differentiation and attenuates α-myosin-specific T cell-mediated myocarditis in mice","authors":"Siqi Li, Kazuko Tajiri, Zixun Yuan, Yoshiko Murakata, Zonghu Song, Seiya Mizuno, Dongzhu Xu, Nobuyuki Murakoshi","doi":"10.1007/s00395-024-01089-3","DOIUrl":"https://doi.org/10.1007/s00395-024-01089-3","url":null,"abstract":"Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare but potentially fatal immune-related adverse event. Previously, we reported a case of ICI-associated myocarditis with elevated autoantibodies to 4E-binding protein 3 (4E-BP3). Recent studies have suggested that 4E-BP3 may play an important role in tumor development. However, its role in cardiac diseases including myocarditis is unknown. We investigated the role of 4E-BP3 in an autoimmune myocarditis mouse model. Myocarditis was induced in wild-type and 4E-BP3 knockout mice by immunization with murine α-myosin peptide. 4E-BP3 gene expression was upregulated in the heart of myocarditis mouse. We found that genetic deletion of 4E-BP3 attenuated myocardial inflammation, reduced fibrosis area, and improved cardiac function in myocarditis mice. Studies in bone marrow-chimeric mice demonstrated that immune cell-derived 4E-BP3 plays a pivotal role in the pathogenesis of myocarditis. Immune cell transfer experiments revealed that 4E-BP3 deficiency in dendritic cells and CD4+ T cells decreased disease severity in recipient mice. Furthermore, dendritic cells that were deficient in 4E-BP3 exhibited a diminished capacity to produce IL-6 and IL-1β. Naive CD4+ T cells lacking 4E-BP3 had a reduced ability to differentiate into T-helper (Th)1 and Th17 cells. These findings suggest that 4E-BP3 in dendritic cells and CD4+ T cells may be critically involved in the pathogenesis of α-myosin-specific T cell-mediated myocarditis. Thus, 4E-BP3 could be a possible therapeutic target for myocarditis.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"38 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of sex and obesity on immune checkpoint inhibition-related cardiac systolic dysfunction in aged mice 性别和肥胖对老年小鼠与免疫检查点抑制相关的心脏收缩功能障碍的影响

IF 9.5 1区医学

Basic Research in Cardiology Pub Date : 2024-11-08 DOI: 10.1007/s00395-024-01088-4

Nabil V. Sayour, Dániel Kucsera, Ayham R. Alhaddad, Viktória É. Tóth, Tamás G. Gergely, Tamás Kovács, Zsombor I. Hegedűs, Márk E. Jakab, Péter Ferdinandy, Zoltán V. Varga

{"title":"Effects of sex and obesity on immune checkpoint inhibition-related cardiac systolic dysfunction in aged mice","authors":"Nabil V. Sayour, Dániel Kucsera, Ayham R. Alhaddad, Viktória É. Tóth, Tamás G. Gergely, Tamás Kovács, Zsombor I. Hegedűs, Márk E. Jakab, Péter Ferdinandy, Zoltán V. Varga","doi":"10.1007/s00395-024-01088-4","DOIUrl":"https://doi.org/10.1007/s00395-024-01088-4","url":null,"abstract":"Despite accumulating data on underlying mechanisms, the influence of sex and prevalent cardio-metabolic co-morbidities on the manifestation and severity of immune checkpoint inhibitor (ICI)-induced cardiotoxicity has not been well defined. To elucidate whether sex and prevalent cardio-metabolic co-morbidities affect ICI-induced cardiotoxicity, we randomized 17-month-old male and female mice to receive control diet (CON) or high-fat diet (HFD) + L-NAME—a well-established mouse model of cardio-metabolic co-morbidities—for 17 weeks (n = 5–7), and evaluated markers of T-cell function in the spleen. As expected, HFD + L-NAME significantly increased body- and heart weight, and serum cholesterol levels, and caused no systolic dysfunction, however, led to diastolic dysfunction, cardiomyocyte hypertrophy, and increased fibrosis only in males compared to corresponding CON. Western blot analyses of splenic immune checkpoint protein levels showed differential expression depending on sex and prevalent cardio-metabolic co-morbidities, suggesting T-cell exhaustion in both sexes on HFD + L-NAME, but more pronounced in males. In a sub-study with a similar setup, we tested cardiotoxic manifestations of ICI by treating mice with anti-PD-1 monoclonal antibody (ICI) for the last 2 weeks of diet administration (n = 5–7). After 2 weeks of ICI treatment, cardiac systolic functions significantly decreased in CON, but not in HFD + L-NAME groups of both sexes compared to baseline (before ICI administration). In conclusion, in this exploratory study using aged mice, we describe for the first time that ICI-related systolic dysfunction is diminished in both sexes when obesity and hypercholesterolemia are present, possibly due to obesity-related T-cell exhaustion.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"215 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-cell transcriptome unveils unique transcriptomic signatures of human organ-specific endothelial cells 单细胞转录组揭示人体器官特异性内皮细胞的独特转录组特征

IF 9.5 1区医学

Basic Research in Cardiology Pub Date : 2024-11-07 DOI: 10.1007/s00395-024-01087-5

Rui-Ze Niu, Hong-Yan Xu, Hui Tian, Dan Zhang, Chun-Yu He, Xiao-Lan Li, Yu-Ye Li, Juan He

{"title":"Single-cell transcriptome unveils unique transcriptomic signatures of human organ-specific endothelial cells","authors":"Rui-Ze Niu, Hong-Yan Xu, Hui Tian, Dan Zhang, Chun-Yu He, Xiao-Lan Li, Yu-Ye Li, Juan He","doi":"10.1007/s00395-024-01087-5","DOIUrl":"https://doi.org/10.1007/s00395-024-01087-5","url":null,"abstract":"The heterogeneity of endothelial cells (ECs) across human tissues remains incompletely inventoried. We constructed an atlas of > 210,000 ECs derived from 38 regions across 24 human tissues. Our analysis reveals significant differences in transcriptome, phenotype, metabolism and transcriptional regulation among ECs from various tissues. Notably, arterial, venous, and lymphatic ECs shared more common markers in multiple tissues than capillary ECs, which exhibited higher heterogeneity. This diversity in capillary ECs suggests their greater potential as targets for drug development. ECs from different tissues and vascular beds were found to be associated with specific diseases. Importantly, tissue specificity of EC senescence is more determined by somatic site than by tissue type (e.g. subcutaneus adipose tissue and visceral adipose tissue). Additionally, sex-specific differences in brain EC senescence were observed. Our EC atlas offers valuble resoursce for identifying EC subclusters in single-cell datasets from body tissues or organoids, facilitating the screen of tissue-specific targeted therapies, and serving as a powerful tool for future discoveries.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"80 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0