Journal of molecular and cellular cardiology plus最新文献

{"title":"Bioinformatics tools for drug repurposing: a tutorial using heart failure as a case study","authors":"Ivo Fonseca ,&nbsp;Fábio Trindade ,&nbsp;Mário Santos ,&nbsp;Adelino Leite-Moreira ,&nbsp;Daniel Moreira-Gonçalves ,&nbsp;Rui Vitorino ,&nbsp;Rita Ferreira ,&nbsp;Rita Nogueira-Ferreira","doi":"10.1016/j.jmccpl.2025.100460","DOIUrl":"10.1016/j.jmccpl.2025.100460","url":null,"abstract":"<div><h3>Purpose</h3><div>Drug repurposing is a crucial strategy for researchers worldwide to accelerate drug development and mitigate associated risks and costs. Heart failure (HF) is a major global health problem with high prevalence and mortality rates. There are significant sex differences in HF, including in the risk factors and phenotype, which demand a sex-personalized drug treatment. A convenient approach in that direction is the reuse of drugs already approved for other conditions that are known to interact in sex-biased dysregulated pathways in HF. Numerous bioinformatics tools can help identify those candidates. This tutorial explores the utility of specific bioinformatics tools in identifying drugs to treat HF as a case study.</div></div><div><h3>Methods</h3><div>Herein, we explain how NeDRex helps identify genes associated with disease and drug repurposing and how functional enrichment analysis can be performed with ShinyGO. We also explain how to predict targets of small bioactive molecules with SwissTargetPrediction and how to retrieve known and predicted interactions between chemicals and proteins with STITCH.</div></div><div><h3>Results</h3><div>The tutorial demonstrates the use of these tools in searching for new HF treatments.</div></div><div><h3>Conclusion</h3><div>This tutorial is designed to ease entry into the utilization of the mentioned bioinformatics tools. This approach can also set a precedent for applying such tools to other diseases. The results presented in this tutorial are illustrative and do not constitute definitive evidence. They are intended for demonstration purposes only.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100460"},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144322791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of human living myocardial slices culture-induced adaptations: a translational perspective","authors":"Jort S.A. van der Geest ,&nbsp;Ernest Diez Benavente ,&nbsp;Willem B. van Ham ,&nbsp;Pieter A. Doevendans ,&nbsp;Linda W. van Laake ,&nbsp;Teun P. de Boer ,&nbsp;Vasco Sampaio-Pinto ,&nbsp;Joost P.G. Sluijter","doi":"10.1016/j.jmccpl.2025.100465","DOIUrl":"10.1016/j.jmccpl.2025.100465","url":null,"abstract":"<div><div>Heart failure involves complex pathophysiological processes, best studied in multicellular human cardiac tissues that reflect the native cellular composition and microenvironment. However, maintaining primary cells and tissues in culture for extended periods remains challenging. Developing robust human cardiac models is critical for advancing preclinical research and bridging the gap to clinical applications. This study aims to characterize adaptations occurring in human living myocardial slices (LMS) during <em>ex vivo</em> culture.</div><div>During culture, LMS demonstrated progressive enhancements in contractile function including stronger force generation, reduced diastolic tension, and faster contraction-relaxation kinetics. However, excitability and force-frequency response decreased over the same period. Cultured LMS showed enhanced calcium handling, including increased ability to follow pacing, higher amplitude, and faster, more stable calcium re-uptake. Structurally, LMS displayed no changes in sarcomeres, cell-cell connections, or mitochondria, despite gene expression changes in cytoskeletal and extracellular matrix-related pathways. Transcriptomic analysis revealed metabolic activation with upregulation of metabolism-related pathways. Interestingly, LMS exhibited increased expression of genes associated with early cardiac development after the culture period.</div><div>LMS provide a powerful translational model for cardiovascular research, enabling the evaluation of novel therapies and fundamental studies. However, culture-induced adaptations must be carefully considered when interpreting results to ensure physiological and disease relevance.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100465"},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144307061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pericellular oxygen dynamics in human cardiac fibroblasts and iPSC-cardiomyocytes in high-throughput plates: insights from experiments and modeling","authors":"Weizhen Li ,&nbsp;David McLeod ,&nbsp;Sarah Antonevich,&nbsp;Maria R. Pozo,&nbsp;Zhenyu Li,&nbsp;Emilia Entcheva","doi":"10.1016/j.jmccpl.2025.100464","DOIUrl":"10.1016/j.jmccpl.2025.100464","url":null,"abstract":"<div><div>Adequate oxygen supply is crucial for proper cellular function. The emergence of high-throughput (HT) expansion of human stem-cell-derived cells and HT in vitro cellular assays for drug testing necessitate monitoring and understanding of the oxygenation conditions, yet virtually no data exists for such settings. We used HT label-free optical measurements and computational modeling to gain insights about oxygen availability (pericellular oxygen dynamics) in syncytia of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) and human cardiac fibroblasts (cFB) grown in glass-bottom 96-well plates under static conditions. Our experimental results highlight the critical role of cell density and solution height (oxygen delivery path) in pericellular oxygen dynamics. The developed computational model, trained on the obtained comprehensive data set, revealed that time-variant maximum oxygen consumption rate, V_max, is needed to faithfully capture the complex pericellular oxygen dynamics in the excitable hiPSC-CMs, but not in the cFBs. Interestingly, hypoxia (&lt;2 % pericellular oxygen) developed within hours in the dense iPSC-CM cultures when the solution volume was sufficiently large. Conversely, hiPSC-CMs grown at low cell density or in smaller solution volume, as well as cFB under all studied conditions, were found to operate in hyperoxic (&gt;7 %) conditions. Pericellular oxygen dynamics of the differentiated hiPSC-CMs evolved over days in culture, with the best improvement in respiration seen in samples operating close to normoxia. Our results and the developed computational model can be used directly to optimize cardiac cell growth in HT plates and achieve desired physiological conditions, which is important in cellular assays for cardiotoxicity, drug development, personalized medicine and heart regeneration applications.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100464"},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144307140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of ventricular activation by subthreshold delayed afterdepolarizations in RyR2-R420Q catecholaminergic polymorphic ventricular tachycardia","authors":"Ewan D. Fowler ,&nbsp;Salimata L. Diakite ,&nbsp;Ana M. Gomez ,&nbsp;Michael A. Colman","doi":"10.1016/j.jmccpl.2025.100466","DOIUrl":"10.1016/j.jmccpl.2025.100466","url":null,"abstract":"<div><h3>Background</h3><div>Catecholaminergic polymorphic ventricular tachycardia (CPVT) carries increased risk of ventricular arrhythmias due to altered Ca²⁺ regulation associated with mutations in the ryanodine receptor (RyR2). Increased Ca²⁺ leak is believed to result in diastolic Ca²⁺ waves and delayed afterdepolarization (DADs) in cardiac myocytes, but it is uncertain how these cellular events induce ventricular tachycardia in the whole heart. We utilised a transgenic mouse model of human RyR2-R420Q (R420Q) CPVT mutation and a range of electrical and optical mapping technologies to examine the role of DAD-induced conduction abnormalities.</div></div><div><h3>Methods</h3><div>Heterozygous R420Q and wildtype (WT) control hearts were perfused on a Langendorff apparatus. Electrical activity was monitored using volume conducted ECG electrodes and monophasic action potential (MAP) electrode recordings. Left ventricular activation and membrane potential changes were recorded using an 8 × 8 multielectrode array and optical mapping, respectively.</div></div><div><h3>Results</h3><div>ECG recordings showed spontaneous ventricular arrhythmias in isolated R420Q hearts. More severe arrhythmias occurred in R420Q hearts following rapid electrical pacing combined with isoproterenol stimulation. Ventricular activation time was not different between genotypes, regardless of stimulation frequency or isoproterenol. Phase differences in local activation times were greater in R420Q hearts during 10 Hz pacing with isoproterenol, suggesting local conduction slowing. Optical mapping experiments revealed subthreshold DADs occurring in R420Q hearts during diastolic pauses. DADs prolonged the subsequent action potential and were associated with conduction slowing during the second beat after the DAD, but not the first beat. 2D tissue simulations revealed that direct inactivation of I_Na during DADs, or indirectly via cycle length dependent refractory mechanisms could account for local conduction slowing.</div></div><div><h3>Conclusions</h3><div>Increased activation dispersion could arise from subthreshold DADs in R420Q mouse hearts and may contribute to conduction block. This could increase the propensity for re-entrant arrhythmias in CPVT without directly triggering ectopic beats.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100466"},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144322792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blueprint of the distinct metabolite profiles of healthy pig heart chambers","authors":"Retu Haikonen ,&nbsp;Topi Meuronen ,&nbsp;Ville Koistinen ,&nbsp;Olli Kärkkäinen ,&nbsp;Tomi Tuomainen ,&nbsp;Gloria I Solano-Aguilar ,&nbsp;Joseph F. Urban Jr. ,&nbsp;Marko Lehtonen ,&nbsp;Pasi Tavi ,&nbsp;Kati Hanhineva","doi":"10.1016/j.jmccpl.2025.100462","DOIUrl":"10.1016/j.jmccpl.2025.100462","url":null,"abstract":"<div><div>The heart is one of the most studied organs, with physiological processes and disease research. While it is well-established that significant structural and functional differences exist between the chambers, most studies focus on only a single heart chamber, predominantly the left ventricle. This study aims to comprehensively characterise the chamber-specific metabolic profiles of all four heart chambers in a healthy animal model close to human metabolism, pigs. We employed liquid chromatography-mass spectrometry metabolomics to analyse the metabolite profiles of heart chambers in healthy pigs (<em>N</em> = 30) maintained on an ad libitum diet and housed under standard, non-stressed physiological conditions. Our findings reveal a higher energy demand in the left ventricle, as evidenced by elevated levels of electron transport chain-related metabolites such as NAD⁺ and FAD. Additionally, hexose-phosphates and several acylcarnitines exhibited chamber-dependent variations in abundance. The ventricles, particularly the left, demonstrated distinct redox states, with differential levels of glutathione and ascorbic acid, suggesting variations in oxidative stress across chambers. Furthermore, amino acids had chamber-specific abundance patterns, and ventricles showed an increased requirement for protein synthesis, likely associated with repair mechanisms following reactive oxygen species (ROS)-induced cellular damage. Our study reveals significant differences in the metabolic profiles across four heart chambers in healthy pig hearts, underscoring the metabolic heterogeneity of cardiac tissue. These findings highlight the necessity of investigating chamber-specific metabolic pathways to better understand heart functionality. Such insights could inform the development of more precise therapeutic strategies tailored to metabolic demands and functional roles in heart chambers.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100462"},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure","authors":"Nadina R. Latchman ,&nbsp;Tyler L. Stevens ,&nbsp;Kenneth C. Bedi ,&nbsp;Benjamin L. Prosser ,&nbsp;Kenneth B. Margulies ,&nbsp;John W. Elrod","doi":"10.1016/j.jmccpl.2025.100461","DOIUrl":"10.1016/j.jmccpl.2025.100461","url":null,"abstract":"<div><h3>Background</h3><div>Cardiomyocyte structural remodeling is reported as a causal contributor to heart failure (HF) development and progression. Growing evidence highlights the role of organelle apposition in cardiomyocyte function and homeostasis. Disruptions in organelle crosstalk, such as that between the sarcoplasmic reticulum (SR) and mitochondria, dysregulate numerous cellular processes that include calcium handling and cellular bioenergetics, two processes that are disrupted and implicated in cardiac pathophysiology. While the physical distance between organelles is thought to be essential for homeostatic cardiomyocyte function, whether the interactions and coupling of organelles are altered in human heart failure remains unclear.</div></div><div><h3>Methods</h3><div>Here, we utilized transmission electron microscopy to characterize the role of organelle apposition in cardiomyocytes from patients with various etiologies of HF. Subsequently, we employed molecular approaches to examine expression changes of proposed organelle tethers.</div></div><div><h3>Results</h3><div>We demonstrate that cardiomyocytes from dilated cardiomyopathy, hypertrophic cardiomyopathy and ischemic cardiomyopathy hearts display smaller, rounded mitochondria as compared to nonfailing controls. Failing cardiomyocytes also exhibited disrupted SR-mitochondria juxtaposition and changes in the expression of various proposed molecular tethers. Further analysis revealed alterations in lipid droplet dynamics including decreased lipid droplet number and less lipid droplets in association with mitochondria in failing cardiomyocytes.</div></div><div><h3>Conclusion</h3><div>We observed dysregulated organelle dynamics which was conserved across various etiologies of heart failure. Our results suggest that organelle structure and apposition is a possible contributor to human HF progression.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100461"},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144270704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic deletion or pharmacological inhibition of acetyl-CoA carboxylase 2 enhances fatty acid oxidation and improves cardiac function and survival in the murine ATGL knockout model of severe heart failure","authors":"Mai Usui ,&nbsp;Yu Tsurekawa ,&nbsp;Tatsuya Ikehara ,&nbsp;Atsuyuki Shimazaki ,&nbsp;Archana Vijayakumar ,&nbsp;Robert P. Myers ,&nbsp;G. Mani Subramanian ,&nbsp;Eisuke Murakami","doi":"10.1016/j.jmccpl.2025.100459","DOIUrl":"10.1016/j.jmccpl.2025.100459","url":null,"abstract":"<div><div>Impaired myocardial energetics, including fatty acid oxidation (FAO), is a hallmark feature in the pathophysiology of various disorders. Deficiency of adipose triglyceride lipase (ATGL) results in impaired FAO which leads to severe heart failure due to massive triglyceride accumulation in cardiac muscle and coronary vasculature. Acetyl-CoA carboxylase 2 (ACC2) is a mitochondrial enzyme that regulates FAO; ACC2 inhibition increases transport of fatty acids into mitochondria for oxidation. In this study, the murine ATGL knockout (KO) model of severe heart failure was used to evaluate the effects ACC2 inhibition induced by whole body genetic KO (<em>Atgl/Acc2</em> double KO mice) and pharmacological inhibition with TLC-3595, an oral, selective small molecule inhibitor of ACC2. Both genetic deletion of <em>Acc2</em> and treatment with TLC-3595 in <em>Atgl</em> KO mice promoted mitochondrial FAO, reduced cardiac lipid accumulation and remodeling, and led to significant improvements in cardiac function, locomotor activity, and survival. Metabolite profiling of cardiac tissue of <em>Atgl/Acc2</em> double KO mice and <em>Atgl</em> KO mice treated with TLC-3595 revealed ACC2-specific changes, including reduced malonyl-CoA and increased short-, medium-, and long-chain acylcarnitines, consistent with improved FAO. These findings support the therapeutic targeting of ACC2 for the treatment of heart failure associated with impaired FAO.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"13 ","pages":"Article 100459"},"PeriodicalIF":0.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is boosting OXPHOS/FAO gene pathways the final end-mechanism of SGLT2i protection?","authors":"Xin Hu,&nbsp;Coert J. Zuurbier","doi":"10.1016/j.jmccpl.2025.100297","DOIUrl":"10.1016/j.jmccpl.2025.100297","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100297"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144270329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JMCC plus - Celebrating milestones and looking ahead in our third year","authors":"Davor Pavlovic ,&nbsp;Rebekah Gundry","doi":"10.1016/j.jmccpl.2025.100286","DOIUrl":"10.1016/j.jmccpl.2025.100286","url":null,"abstract":"","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100286"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144270328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoform switch of T-cell factor7L2 during mouse heart development","authors":"Bo Ye ,&nbsp;Lu Xiao ,&nbsp;Yuyong Xu ,&nbsp;Haodong Xu ,&nbsp;Faqian Li","doi":"10.1016/j.jmccpl.2025.100458","DOIUrl":"10.1016/j.jmccpl.2025.100458","url":null,"abstract":"<div><div>Canonical WNT signaling plays critical, often opposing roles in heart development and disease, but its context-dependent mechanisms remain unclear. We hypothesized that alternative splicing of Tcf7l2, a key nuclear partner of β-catenin, contributes to WNT signaling specificity in the heart. To investigate this, we cloned and sequenced 53 Tcf7l2 transcripts in ventricular tissues from embryonic day 17.5 (E17.5, 24/53) and postnatal day 8 (P8, 29/53) mice, identifying 32 distinct isoforms. Among 18 potential exons, exons 6 and 17 were absent, and over 80 % of transcripts lacked exon 4. Alternative splicing was prominent in the C-terminal exons (14, 15, and 16), with exon 14 inclusion significantly higher in P8 hearts (64.3 %) than E17.5 hearts (34.8 %). Variations in exon 15 and 16 combinations, along with reading frame shifts caused by the adenine insertion and deletion (indel) near the beginning of exon 18, affected C-terminal structures, altering the presence of the E-tail, C-clamp, and CtBP-binding motifs. Notably, exon 14 insertion introduced a redox-switch domain spanning the NLS and C-clamp regions in E and S isoforms, while adenine indels altered isoform lengths, driving transitions between E, S, and M isoforms. RT-PCR validation across multiple developmental stages confirmed these splicing patterns. Our findings suggest that a postnatal redox-sensitive isoform switch in Tcf7l2 modulates WNT signaling, potentially influencing cardiomyocyte maturation during the transition from proliferation to hypertrophy.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100458"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144189693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}