Journal of molecular and cellular cardiology plus最新文献

{"title":"Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in mice","authors":"Tetsuro Marunouchi,&nbsp;Mayu Kyono,&nbsp;Naoko Kikuchi,&nbsp;Kouichi Tanonaka","doi":"10.1016/j.jmccpl.2025.100292","DOIUrl":"10.1016/j.jmccpl.2025.100292","url":null,"abstract":"<div><div>The size of the infarct area following acute myocardial infarction (AMI) is a critical prognostic factor. Caspase-11-dependent pyroptosis has been implicated as a key mechanism driving cardiomyocyte death after AMI. However, no therapeutic agents have been developed to inhibit myocardial cell death by targeting caspase-11. This study investigates the effects of gemfibrozil, a potential caspase-11 inhibitor, on ischemia/reperfusion-induced myocardial pyroptosis in mice. To model AMI, the left coronary artery of C57BL/6 N mice was ligated for 1 h, followed by reperfusion. Levels of cleaved caspase-11 and the N-terminal fragment of gasdermin D (GSDMD-N) in ischemic myocardial tissue increased progressively over time after ischemia/reperfusion. Gemfibrozil treatment during reperfusion significantly attenuated these increases in cleaved caspase-11 and GSDMD-N levels. Moreover, gemfibrozil reduced the extent of myocardial infarct size during reperfusion. In cultured cardiomyocytes isolated from adult mice, hypoxia/reoxygenation-induced increases in caspase-11 and GSDMD cleavage were similarly mitigated by gemfibrozil, which concurrently prevented necrotic cell death. These findings demonstrate the involvement of caspase-11-dependent pyroptosis in myocardial cell death following ischemia/reperfusion and suggest that gemfibrozil holds promise as a therapeutic agent for reducing myocardial infarct size after AMI.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100292"},"PeriodicalIF":0.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovations in heart failure management: The role of cutting-edge biomarkers and multi-omics integration","authors":"Jose Mesquita Bastos ,&nbsp;Beatriz Colaço ,&nbsp;Rui Baptista ,&nbsp;Cristina Gavina ,&nbsp;Rui Vitorino","doi":"10.1016/j.jmccpl.2025.100290","DOIUrl":"10.1016/j.jmccpl.2025.100290","url":null,"abstract":"<div><div>Heart failure (HF) remains a major cause of morbidity and mortality worldwide and represents a major challenge for diagnosis, prognosis and treatment due to its heterogeneity. Traditional biomarkers such as BNP and NT-proBNP are valuable but insufficient to capture the complexity of HF, especially phenotypes such as HF with preserved ejection fraction (HFpEF). Recent advances in multi-omics technology and novel biomarkers such as cell-free DNA (cfDNA), microRNAs (miRNAs), ST2 and galectin-3 offer transformative potential for HF management. This review explores the integration of these innovative biomarkers into clinical practice and highlights their benefits, such as improved diagnostic accuracy, enhanced risk stratification and non-invasive monitoring capabilities. By leveraging multi-omics approaches, including lipidomics and metabolomics, clinicians can uncover new pathways, refine the classification of HF phenotypes, and develop personalized therapeutic strategies tailored to individual patient profiles. Remarkable advances in proteomics and metabolomics have identified biomarkers associated with key HF mechanisms such as mitochondrial dysfunction, inflammation and fibrosis, paving the way for targeted therapies and early interventions. Despite the promising results, significant challenges remain in translating these findings into routine care, including high costs, technical limitations and the need for large-scale validation studies. This report argues for an integrative, multi-omics-based model to overcome these obstacles and emphasizes the importance of collaboration between researchers, clinicians and policy makers. By linking innovative science with practical applications, multi-omics approaches have the potential to redefine HF management and lead to better patient outcomes and more sustainable healthcare systems.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"11 ","pages":"Article 100290"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degeneration","authors":"Timothy J. Mead ,&nbsp;Sumit Bhutada ,&nbsp;Niccolò Peruzzi ,&nbsp;Janet Adegboye ,&nbsp;Deborah E. Seifert ,&nbsp;Elisabeth Cahill ,&nbsp;Jeanne Drinko ,&nbsp;Eoin Donnellan ,&nbsp;Anu Guggiliam ,&nbsp;Zoran Popovic ,&nbsp;Brian Griffin ,&nbsp;Karin Tran-Lundmark ,&nbsp;Suneel S. Apte","doi":"10.1016/j.jmccpl.2025.100288","DOIUrl":"10.1016/j.jmccpl.2025.100288","url":null,"abstract":"<div><div>The physiological roles of the metalloprotease-proteoglycan ADAMTS7, a drug target in atherosclerosis and vascular restenosis, and its homolog ADAMTS12, are undefined in the cardiovascular system. The objective of the present work was to investigate their roles in mice with genetic inactivation of both proteases and in relation to the resulting valve defects, to define their proteolytic activities in the matrisome. Here, we demonstrate that <em>Adamts7</em> and <em>Adamts12</em> are co-expressed in heart valves and each buffers inactivation of the other by compensatory upregulation. Leaflets of <em>Adamts7</em>^−/−;<em>Adamts12</em>^−/− aortic valves, but not the respective single mutants, were abnormally shaped at birth, with progressively severe disorganization and enlargement occurring thereafter. Doppler echocardiography showed that <em>Adamts7</em>^−/−;<em>Adamts12</em>^−/− mice had stenotic and regurgitant aortic valves. We investigated ADAMTS7 and ADAMTS12 substrates relevant to the valve matrisome in secretome libraries from <em>Adamts7</em>^−/−;<em>Adamts12</em>^−/− cells using the N-terminomics technique Terminal Amine Isotopic Labeling of Substrates (TAILS). Although ADAMTS7 and ADAMTS12 shared several extracellular matrix (ECM) substrates, cleavage sites and sequence preference for each protease were distinct. <em>Adamts7</em>^−/−;<em>Adamts12</em>^−/− valve leaflets showed accumulation of several of the identified ECM substrates, including periostin, a matricellular protein crucial for cardiac valve homeostasis. We conclude that the myxomatous degeneration in <em>Adamts7</em>^−/−;<em>Adamts12</em>^−/− valve leaflets reflects a complex disturbance of ECM proteostasis with accumulation of multiple ADAMTS7 and ADAMTS12 ECM substrates, and perturbation of regulatory pathways with roots in ECM, such as TGFβ signaling, which was increased in the mutant valves.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"11 ","pages":"Article 100288"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of Snord116 protects cardiomyocyte kinetics during ischemic stress","authors":"Lucy E. Pilcher ,&nbsp;Emmaleigh Hancock ,&nbsp;Akshay Neeli ,&nbsp;Maria Sckolnick ,&nbsp;Matthew A. Caporizzo ,&nbsp;Bradley M. Palmer ,&nbsp;Jeffrey L. Spees","doi":"10.1016/j.jmccpl.2025.100291","DOIUrl":"10.1016/j.jmccpl.2025.100291","url":null,"abstract":"<div><div>Loss of Snord116, a non-coding RNA, causes Prader Willi Syndrome (PWS), a complex disorder with circadian, metabolic, neurologic, and cardiovascular phenotypes. The Snord116 paternal knockout (Snord116p-) mouse, a model of PWS, demonstrated differential methylation of thousands of genes involved in regulation of metabolism, epigenetics, and ion homeostasis. To determine if Snord116 expression influences the cardiomyocyte response to acute ischemia, we developed a model of ischemia and reperfusion using living myocardial slices and monitored cardiomyocyte function in slices derived from Snord116p- mice and wildtype littermates (WT LM) of both sexes. We found that Snord116 loss reduced ischemia-induced systolic prolongation and delayed diastolic elongation in slices from both males and females. Furthermore, when compared with slices from males, slices from females experienced a greater increase in end-diastolic force after ischemia. We conclude that female myocardium responds more dramatically and quickly to ischemic injury in this model and that loss of Snord116 is cardioprotective; this allows for a more complete myocardial recovery following reperfusion.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"11 ","pages":"Article 100291"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFNγ activates an immune-like regulatory network in the cardiac vascular endothelium","authors":"Timothy D. Arthur ,&nbsp;Isaac N. Joshua ,&nbsp;Jennifer P. Nguyen ,&nbsp;Agnieszka D'Antonio-Chronowska ,&nbsp;Matteo D'Antonio ,&nbsp;Kelly A. Frazer","doi":"10.1016/j.jmccpl.2025.100289","DOIUrl":"10.1016/j.jmccpl.2025.100289","url":null,"abstract":"<div><div>The regulatory mechanisms underlying the response to pro-inflammatory cytokines in cardiac diseases are poorly understood. Here, we use iPSC-derived cardiovascular progenitor cells (CVPCs) to model the response to interferon gamma (IFNγ) in human cardiac tissue. We generate RNA-seq and ATAC-seq for four CVPCs that were treated with IFNγ and compare them with paired untreated controls. Transcriptional differences after treatment show that IFNγ initiates an innate immune cell-like response, shifts the CVPC transcriptome toward coronary artery and aorta profiles, and stimulates expression of endothelial cell-specific genes. Analysis of the accessible chromatin shows that IFNγ is a potent chromatin remodeler and establishes an IRF-STAT immune-cell like regulatory network. Finally, we show that 11 GWAS risk variants for 8 common cardiac diseases overlap IFNγ-upregulated ATAC-seq peaks. Our findings reveal insights into IFNγ-induced activation of an immune-like regulatory network in human cardiac tissue and the potential role that regulatory elements in this pathway play in common cardiac diseases.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"11 ","pages":"Article 100289"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiotensin IV does not exert prothrombotic effects in vivo","authors":"Qifang Wu ,&nbsp;Christine Gille ,&nbsp;Florian Maderspacher ,&nbsp;Bianca Hildebrand ,&nbsp;Manuela Thienel ,&nbsp;Sebastian Clauss","doi":"10.1016/j.jmccpl.2025.100287","DOIUrl":"10.1016/j.jmccpl.2025.100287","url":null,"abstract":"<div><div>Thrombosis and thromboembolism are serious clinical complications of cardiovascular diseases and are among the leading causes of mortality worldwide. Dysregulation of the renin-angiotensin system is associated with an increased incidence of thrombotic events. Angiotensin II (AngII) is known to enhance platelet aggregation, contributing to a prothrombotic state in patients. Important biological roles of other angiotensin peptides and their receptors have been shown, but their specific role in thrombus formation remains unclear. Recent evidence suggests a prothrombotic role of angiotensin IV (AngIV). To confirm the prothrombotic effects of AngIV and to further investigate AngIV-mediated mechanisms, we utilized osmotic minipumps to administer AngIV in mice continuously over 4 weeks. AngIV treatment did not induce thrombus formation in the heart, did not affect platelet numbers, and did not enhance platelet aggregation. HGF, c-MET, or PAI-1 expression levels in the heart were not affected by AngIV treatment in mice. Furthermore, we did not observe altered platelet aggregation of human platelets incubated with HGF. These findings indicate that AngIV does not regulate key prothrombotic mechanisms.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"11 ","pages":"Article 100287"},"PeriodicalIF":0.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-depth proteomic profiling identifies potentiation of the LPS response by 7-ketocholesterol","authors":"Iain R. Phair ,&nbsp;Magdalena Sovakova ,&nbsp;Noor Alqurashi ,&nbsp;Raid B. Nisr ,&nbsp;Alison D. McNeilly ,&nbsp;Douglas Lamont ,&nbsp;Graham Rena","doi":"10.1016/j.jmccpl.2025.100285","DOIUrl":"10.1016/j.jmccpl.2025.100285","url":null,"abstract":"<div><div>In patients with stable coronary artery disease, plasma levels of 7-ketocholesterol (7-KC), found at high levels in atherosclerotic lesions, predict risk of incident heart failure dose dependently, potentially contributing to disease aetiology. Previous studies demonstrated that 7-KC can elicit effects on macrophage function; however, effects of 7-KC on the macrophage proteome have not been studied systematically. Here we used quantitative mass spectrometry to establish the effect of 7-KC on the mouse macrophage proteome. 7-KC independently mediated dynamic changes, including on atherogenic/M1 markers, cholesterol metabolism, biosynthesis and transport, as well as nutrient transport more broadly. These changes were however insufficient alone to drive changes in cytokine and chemokine secretion. Rather, they prime the macrophage, potentiating LPS-stimulated TNF alpha secretion and key pro-inflammatory enzymes. Our results indicate that 7-KC has independent metabolic effects on the macrophage; however, effects on the immune system are primarily due to the changes in metabolism priming the response to an inflammatory stimulus. Earlier findings from CANTOS and the recent FDA approval of colchicine highlight that inflammation is a viable target for cardiovascular disease; however, it is currrently unclear which will be the best anti-inflammatory targets to pursue in the future. In this context, our findings suggest that drugs targeting atherogenic markers induced by 7-KC might be well tolerated, as they will not necessarily be expected to be immunosuppressive.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"11 ","pages":"Article 100285"},"PeriodicalIF":0.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143164833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating levels of miR-20b-5p are associated with survival in cardiogenic shock","authors":"Tuomas Mäntylä ,&nbsp;Chunguang Wang ,&nbsp;Mikko Hänninen ,&nbsp;Katariina Immonen ,&nbsp;Toni Jäntti ,&nbsp;Johan Lassus ,&nbsp;Ilkka Tikkanen ,&nbsp;Kari Pulkki ,&nbsp;Yvan Devaux ,&nbsp;Veli-Pekka Harjola ,&nbsp;Päivi Lakkisto ,&nbsp;CardShock Study Investigators","doi":"10.1016/j.jmccpl.2025.100284","DOIUrl":"10.1016/j.jmccpl.2025.100284","url":null,"abstract":"<div><div>Cardiogenic shock (CS) is a medical emergency with high in-hospital mortality. New biomarkers are needed to identify patients at a greater risk of adverse outcomes. This study aimed to investigate the prognostic potential of microRNAs (miRNAs) in assessment of the outcome of cardiogenic shock.</div><div>Circulating miRNA levels were measured by quantitative PCR in plasma samples collected at baseline from 165 patients of the multicenter, prospective, observational CardShock study and compared between in-hospital and 90-day survivors and non-survivors. Of the 10 studied miRNAs, median levels of miR-20b-5p at baseline were significantly higher in in-hospital and 90-day survivors compared to non-survivors [median 0.014 arbitrary units (AU) (interquartile range (IQR) 0.003–0.024) <em>vs.</em> 0.008 AU (IQR 0.001–0.015), <em>p</em> = 0.013] and [0.015 AU (IQR 0.003–0.025) <em>vs.</em> 0.010 AU (IQR 0.001–0.015), <em>p</em> = 0.012], respectively. In Cox regression analysis, miR-20b-5p levels in the highest quartile were significantly associated with 90-day survival (adjusted hazard ratio 2.47 (95 % confidence interval 1.16–5.28), <em>p</em> = 0.019) when adjusted for CardShock Risk Score variables (age, confusion at presentation, previous myocardial infarction or coronary artery bypass grafting, acute coronary syndrome (ACS) etiology, left ventricular ejection fraction, lactate, and estimated glomerular filtration rate). A similar association of highest quartile miR-20b-5p levels with 90-day survival was also confirmed in ACS patient subcohort (79 % of CS patients).</div><div>The results of this study indicate that circulating levels of miR-20b-5p at baseline could help in assessing in-hospital and 90-day survival in CS patients.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"11 ","pages":"Article 100284"},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143164832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep plasma and tissue proteome profiling of knockout mice reveals pathways associated with Svep1 deficiency","authors":"Colleen B. Maxwell ,&nbsp;Nikita Bhakta ,&nbsp;Matthew J. Denniff ,&nbsp;Jatinderpal K. Sandhu ,&nbsp;Thorsten Kessler ,&nbsp;Leong L. Ng ,&nbsp;Donald J.L. Jones ,&nbsp;Tom R. Webb ,&nbsp;Gavin E. Morris","doi":"10.1016/j.jmccpl.2025.100283","DOIUrl":"10.1016/j.jmccpl.2025.100283","url":null,"abstract":"<div><div>Despite strong causal associations with cardiovascular and metabolic disorders including coronary artery disease, hypertension, and type 2 diabetes, as well as a range of other diseases, the exact function of the protein SVEP1 remains largely unknown. Animal models have been employed to investigate how SVEP1 contributes to disease, with a focus on murine models exploring its role in development, cardiometabolic disease and platelet biology. In this study, we aimed to comprehensively phenotype the proteome of <em>Svep1</em>^+/− mice compared to wild-type (WT) littermates using liquid chromatography-tandem mass spectrometry (LC-MS/MS) bottom-up proteomics in plasma, heart, aorta, lung, and kidney to identify dysregulated pathways and biological functions associated with <em>Svep1</em> deficiency. Our findings reveal that <em>Svep1</em> deficiency leads to significant proteomic alterations across the mouse, with the highest number of dysregulated proteins observed in plasma and kidney. Key dysregulated proteins in plasma include upregulation of ADGRV1, CDH1, and MYH6, and downregulation of MTIF2 and AKAP13 which, alongside other proteins dysregulated across tissues, indicate disruption in cell adhesion, extracellular matrix organisation, platelet degranulation, and Rho GTPase pathways. Novel findings include significant enrichment of complement cascades in plasma, suggesting dysregulation of innate immune responses and hemostasis due to <em>Svep1</em> deficiency. Pathways related to chylomicron assembly and lipid metabolism were also enriched. Additionally, we developed a high-throughput quantitative targeted LC-MS/MS assay to measure endogenous levels of murine SVEP1. SVEP1 was detectable in lung homogenate and showed a significant reduction in SVEP1 levels in <em>Svep1</em>^+/− <em>vs.</em> WT, but was not identified in plasma, heart, aorta, or kidney, likely due to expression levels below the assay's detection limit. Overall, this deep phenotyping study provides insight into the systemic impact of <em>Svep1</em> deficiency.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"11 ","pages":"Article 100283"},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated transcriptomic and regulatory RNA profiling reflects complex pathophysiology and uncovers a conserved gene signature in end stage heart failure","authors":"Amit Anand ,&nbsp;Julius Punnen ,&nbsp;U.M. Nagamalesh ,&nbsp;Sabariya Selvam ,&nbsp;Madhusudhan Bysani ,&nbsp;Ramya Venkatesh ,&nbsp;Kriti Nawin ,&nbsp;Shilpa Garg ,&nbsp;Bagirath Raghuraman ,&nbsp;Varun Shetty ,&nbsp;Senthil Kumaran ,&nbsp;Manoj Dokania ,&nbsp;Pradeep Narayan ,&nbsp;Ankita Udwadia ,&nbsp;Kushan Gunawardhana ,&nbsp;David Gordon ,&nbsp;Manjunath Ramarao ,&nbsp;Lei Zhao ,&nbsp;Jyoti Gulia","doi":"10.1016/j.jmccpl.2025.100282","DOIUrl":"10.1016/j.jmccpl.2025.100282","url":null,"abstract":"<div><h3>Background</h3><div>Heart failure (HF) is a complex syndrome. Despite availability of multiple treatment options, the mortality remains high and the quality of life poor. Better understanding of the underlying pathophysiological processes can lead to development of novel therapies. Multiple comparative transcriptomics studies, which revealed gene level changes in the key pathophysiological pathways in failing hearts, point towards heterogeneity from interplay of disease stage, etiologies and ethnicity. Transcriptomic characterization of HF in patients from different ethnicities can potentially help in understanding the heterogeneity imparted by various factors and the core elements in heart failure.</div></div><div><h3>Methods &amp; results</h3><div>An integrated analysis of bulk transcriptome and microRNA sequencing from the cardiac tissues of 30 South Asian (SA) patients having HF with reduced ejection fraction (HFrEF) and 19 control subjects was conducted. Plasma miRNAs from a subset of HFrEF and control patients were also sequenced to understand their biomarker potential. The altered transcriptome from the myocardium of SA HFrEF patients reflected cardiac muscle contraction, cellular energetics, altered immune signaling and extracellular matrix remodelling as predominant pathophysiological mechanisms. The SA HFrEF patients also showed dysregulation of multiple microRNAs in cardiac tissue like miR-216, miR-217, miR-184 and miR-9983. Many of these miRNAs, such as miR184 and few others, showed altered levels in both the plasma and cardiac tissue of HFrEF patients suggesting their biomarker potential. The diversity in the HFrEF transcriptomes from published studies led us to examine the core HF genes in our cohort. A gene signature generated using machine learning (ML) from the top dysregulated genes in SA HFrEF cohort stratified HF from controls in other cohorts. The sensitivity of the HF gene signature was further improved when union of two cohorts was used as a training set. Our ML analyses developed a core HF gene signature consisting of 21 genes that can stratify HF patients from controls with 98 % sensitivity in all the tested cohorts.</div></div><div><h3>Conclusions</h3><div>This study reveals molecular changes underlying the pathophysiology as reflected by coding and regulatory non-coding components of transcriptome from South Asian patients and uncovers a conserved gene signature for HF.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"11 ","pages":"Article 100282"},"PeriodicalIF":0.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143164831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}