Journal of molecular and cellular cardiology plus最新文献

{"title":"Differential regulation during development, aging, and disease implies heart cell specific functions of the Mediator Complex","authors":"Dominic W. Kolonay ,&nbsp;Chad E. Grueter ,&nbsp;Kedryn K. Baskin","doi":"10.1016/j.jmccpl.2025.100456","DOIUrl":"10.1016/j.jmccpl.2025.100456","url":null,"abstract":"<div><div>Transcription directs the heart's development and adaptation to stress signals, and transcriptional dysregulation contributes to developmental disorders, pathological remodeling and heart failure (HF). Stereotypic changes at the mRNA level in the failing heart can be powerful diagnostics, as dysregulation can precede pathological outcomes such as decreased ejection fraction and increased heart size. The Mediator Complex is a general regulator of transcription in all eukaryotic cells; however, unknown subunit- and tissue-specific functions complicate our understanding of Mediator's influence on the cell. Here, we investigated the subunit-specific responses of Mediator throughout cardiac development, aging, and disease at the single cell- and whole ventricle-resolution using single cell RNA-sequencing, bulk RNA-sequencing, qPCR, and assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) datasets from humans and mice. In the developing heart, we discovered that key stages of growth such as ventricle formation were marked with elevated Mediator component expression, which declined during postnatal maturation, but increased again in the aging heart. Heart failure, a heterogenous disease, presented with a global increase in Mediator expression in human and mouse cardiomyocytes. This increased expression was mirrored by increased chromatin accessibility at the promoters of Mediator genes. Collectively, this study reveals the dynamic expression of Mediator subunits throughout the stages of the cardiomyocyte lifecycle and uncovers potential mechanisms by which Mediator is modulated in response to various pathological stimuli.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100456"},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170390","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":"Perinatal death in pig models of hypertrophic cardiomyopathy carrying sarcomere pathogenic variants","authors":"Tatiana Flisikowska ,&nbsp;Björn Petersen ,&nbsp;Giulia Mearini ,&nbsp;Daniela Huber ,&nbsp;Mayuko Kurome ,&nbsp;Melanie Stoff ,&nbsp;Saskia Schlossarek ,&nbsp;Andrea Lucas-Hahn ,&nbsp;Eckhard Wolf ,&nbsp;Judith Montag ,&nbsp;Angelika Schnieke ,&nbsp;Lucie Carrier","doi":"10.1016/j.jmccpl.2025.100457","DOIUrl":"10.1016/j.jmccpl.2025.100457","url":null,"abstract":"<div><div>Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease caused by genetic variants in sarcomeric proteins, particularly in myosin binding protein C3 (<em>MYBPC3</em>) and myosin heavy chain 7 (<em>MYH7</em>). Less known is that neonatal forms of HCM rapidly evolve into systolic heart failure and death within the first year of life. Although myosin inhibitors are now used to treat obstructive forms of adult HCM, there is still a need for novel therapeutic options and predictive animal models to assess them. Our aim was to model in pigs severe forms of human HCM carrying bi-allelic truncating <em>MYBPC3</em> mutations or heterozygous missense <em>MYH7</em> variants. Pigs were generated by CRISPR/Cas9 genome or cytosine-base editing in porcine fibroblasts combined with somatic cell nuclear transfer. Several pregnancies were established but piglets were non-viable. The <em>MYBPC3</em>-edited piglet exhibited a compound heterozygous mutation leading to a markedly low level of mutant MYBPC3 protein and cardiac hypertrophy, reflecting the situation in infants. The <em>MYH7</em>-edited piglets carried the heterozygous p.Arg453Cys variant and exhibited ventricular hypertrophy. In conclusion, <em>MYBPC3</em> and <em>MYH7</em> cloned piglets developed cardiac hypertrophy and died around birth, indicating that pigs are particularly sensitive to sarcomeric gene mutations.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100457"},"PeriodicalIF":0.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123363","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":"Atrial electrical alterations with intact cardiac structure and contractile function in a mouse model of an HCM-linked ACTN2 variant","authors":"Maya Noureddine ,&nbsp;Sophie Broadway-Stringer ,&nbsp;Christopher O'Shea ,&nbsp;Bethany A.I. Jones ,&nbsp;Abbie Hayes ,&nbsp;Chris Denning ,&nbsp;Siobhan Loughna ,&nbsp;Fiyaz Mohammed ,&nbsp;Davor Pavlovic ,&nbsp;Katja Gehmlich","doi":"10.1016/j.jmccpl.2025.100455","DOIUrl":"10.1016/j.jmccpl.2025.100455","url":null,"abstract":"<div><h3>Background</h3><div>Missense variants of <em>Z</em>-disk protein, alpha-actinin-2 (ACTN2), have been linked to hypertrophic cardiomyopathy (HCM). A novel <em>ACTN2</em> missense variant, M228T, was identified in family members presenting with HCM and/or atrial arrhythmias. Embryonic lethality was previously shown in mice expressing this variant homozygously, whereas heterozygous (Het) expression did not manifest an overt HCM phenotype. Importantly, the atrial arrhythmias observed in the identified family have not been explored in the context of M228T, despite many patients exhibiting electrical abnormalities prior to the clinical onset of HCM.</div></div><div><h3>Methods</h3><div>Six-month-old Het M228T and wild-type (WT) mice were used to evaluate electrophysiological properties using electrocardiography (ECG) and atrial optical mapping. Echocardiography and strain analysis were employed to assess cardiac structure and function.</div></div><div><h3>Results</h3><div>Het mice exhibited a prolongation in action potential duration and depolarisation time at 30, 50, and 70 % repolarisation in both the left and right atria. No significant alterations in atrial conduction velocity were observed. No changes in atrial ECG parameters were detected. Het mice displayed no evidence of structural remodelling, nor were there any changes in systolic parameters or overt diastolic dysfunction, as assessed by conventional echocardiography and strain analysis. Signs of contractile dyssynchrony were present, specifically at the apex relative to WT controls.</div></div><div><h3>Conclusion</h3><div>The Het M228T mouse model demonstrated atrial electrical alterations that occurred independently of any overt cardiac structural or functional remodelling. These findings may support the causative role for atrial electric phenotypes identified in a subset of patients carrying the variant.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100455"},"PeriodicalIF":0.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144139574","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":"Glyoxal is a superior fixative to formaldehyde in promoting antigenicity and structural integrity in murine cardiac tissues","authors":"Allen C.T. Teng ,&nbsp;Dev Mehangrey ,&nbsp;Ava Vandenbelt ,&nbsp;Karl Vearncombe ,&nbsp;Justin D. Callahan ,&nbsp;Priya Mistry ,&nbsp;Wenping Li ,&nbsp;Cristine J. Reitz ,&nbsp;Omar Hamed ,&nbsp;Madison Roche ,&nbsp;Uros Kuzmanov ,&nbsp;Jason E. Fish ,&nbsp;Slava Epelman ,&nbsp;Anthony O. Gramolini","doi":"10.1016/j.jmccpl.2025.100454","DOIUrl":"10.1016/j.jmccpl.2025.100454","url":null,"abstract":"<div><h3>Background</h3><div>Immunofluorescence (IF) is an essential technique for evaluating histological and biochemical changes in tissue specimens. A critical step in IF is sample fixation, typically achieved using formaldehyde-based fixatives, such as 4 % paraformaldehyde (PFA) or 10 % formalin. However, these fixatives are prone to over-fixation, which can alter antigenicity and promote artifacts. This study investigated glyoxal, a two‑carbon dialdehyde, as a potential alternative fixative for murine cardiac tissues for IF and crosslinking immunoprecipitation-mass spectrometry (xIP-MS) applications.</div></div><div><h3>Methods</h3><div>Various concentrations and fixation durations of glyoxal were compared with 4 % PFA. Tissue structural integrity was assessed using Hematoxylin and Eosin (H&amp;E) staining, while antigen preservation in cardiomyocytes was evaluated through fluorescent microscopy. Immunofluorescence of cardiac resident cells, including cardiac fibroblasts, smooth muscle cells, and endothelial cells were also investigated. xIP-MS assays were carried by phospholamban (PLN) immunoprecipitation in glyoxal-fixed mouse hearts, followed by mass spectrometry analysis.</div></div><div><h3>Results</h3><div>Glyoxal showed comparable preservation of cardiac tissue architecture and myofiber integrity to PFA, but with superior antigen retention and protein detection. Fluorescent imaging was performed for sarcoplasmic reticulum markers (SERCA2 and PLN), intercalated disc proteins (N-Cadherin and Cx43), and contractile proteins (F-Actin and MyHC). Quantitative image analysis confirmed that glyoxal enhanced antibody penetration in thicker tissues (30 μm) and maintained the antigenicity of various cardiac resident cell markers. Glyoxal fixation allowed for xIP-MS by lightly crosslinking PLN with its associated protein complexes, enabling the identification of novel PLN-interacting proteins in mouse hearts.</div></div><div><h3>Conclusion</h3><div>Our findings underscore the utility of glyoxal as a superior alternative to PFA in cardiac biochemistry research, offering improvements in the preservation of tissue morphology, antigen detection, and protein complex conservation in murine cardiac tissues.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100454"},"PeriodicalIF":0.0,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069777","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":"Structural and functional characterization of the cardiac mitochondria-associated reticular membranes in the ob/ob mouse model","authors":"Hala Guedouari ,&nbsp;Maya Dia ,&nbsp;Juliette Geoffray ,&nbsp;Camille Brun ,&nbsp;Florentin Moulin ,&nbsp;Lucas Givre ,&nbsp;Lucid Belmudes ,&nbsp;Christelle Leon ,&nbsp;Stephanie Chanon ,&nbsp;Jingwei Ji-Cao ,&nbsp;Christophe Chouabe ,&nbsp;Sylvie Ducreux ,&nbsp;Claire Crola Da Silva ,&nbsp;Ludovic Gomez ,&nbsp;Yohann Couté ,&nbsp;Helene Thibault ,&nbsp;Jennifer Rieusset ,&nbsp;Melanie Paillard","doi":"10.1016/j.jmccpl.2025.100453","DOIUrl":"10.1016/j.jmccpl.2025.100453","url":null,"abstract":"<div><div>Type 2 diabetes (T2D) and obesity strongly lead to diabetic cardiomyopathy (DCM). The involvement of mitochondria-associated reticular membranes (MAMs), a signaling hub in the cardiomyocyte, starts to be demonstrated in T2D-related metabolic disorders. We recently discovered a cardiac MAM Ca²⁺ uncoupling in a high-fat high-sucrose diet (HFHSD)-induced mouse model of DCM. To better determine the role of MAMs in the progression of DCM, we here aimed to characterize the proteomic composition and function of the cardiac MAMs of another obesogenic T2D mouse model, the leptin-deficient <em>ob/ob</em> mouse.</div><div>12-week old male C57Bl6-N <em>ob/ob</em> mice displayed strain rate dysfunction and concentric remodeling, while no change was observed in fractional shortening or diastolic function. Increased lipid deposition but no fibrosis was measured in the <em>ob/ob</em> heart compared to WT. Electron microscopy analysis revealed that cardiac MAM length and width were similar between both groups. A trend towards an increased MAM protein content was measured in the <em>ob/ob</em> heart. MAM proteome analyses showed mainly increased processes in <em>ob/ob</em> hearts: cellular response to stress, lipid metabolism, ion transport and membrane organization. Functionally, MAM-driven Ca²⁺ fluxes were unchanged but hypoxic stress induced a cell death increase in the <em>ob/ob</em> cardiomyocyte. Mitochondrial respiration, cardiomyocyte shortening, ATP and ROS content were similar between groups.</div><div>To conclude, at that age, while being strongly hyperglycemic and insulin-resistant, the <em>ob/ob</em> mouse model rather displays a modest DCM without strong changes in MAMs: preserved structural and functional MAM Ca²⁺ coupling but increased response to stress.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100453"},"PeriodicalIF":0.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089501","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":"Performance horses as a model for exercise-associated cardiac arrhythmias and sudden cardiac death","authors":"Amanda Avison ,&nbsp;Peter W. Physick-Sheard ,&nbsp;W. Glen Pyle","doi":"10.1016/j.jmccpl.2025.100452","DOIUrl":"10.1016/j.jmccpl.2025.100452","url":null,"abstract":"<div><div>This paper reviews the myocardial substrate of horses relative to that of humans and discusses the utility of performance horses as a model of exercise-associated cardiac arrhythmias and sudden cardiac death in athletes. The coronary circulation is similar between the species while coronary artery anomalies and myocardial bridging appear to only be associated with athletic mortality in human athletes and not in performance horses. There are subtle differences in the histology of the sinus and atrioventricular nodes, of unknown clinical significance, while the His bundle is more highly innervated in horses. The equine Purkinje network is much more extensive, contributing to a difference in the mean electrical axis between horses and humans. Differences in ion channel expression have been reported, although they are poorly characterized, and are of unknown clinical significance. However, horses may be a particularly good model to investigate the function of Kv1.5 due to its spontaneous ventricular expression, which is lacking in human ventricles. Similarities in cardiac structure, coronary vasculature, and ability to exercise at high levels makes performance horses a good model to investigate exercise-associated cardiac arrhythmias and sudden cardiac death in athletes. However, differences in myocardial substrate should be taken into consideration when designing studies and interpreting results.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100452"},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937192","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":"Sirtuin 4 accelerates heart failure development by enhancing reactive oxygen species-mediated profibrotic transcriptional signaling","authors":"Nikole J. Byrne ,&nbsp;Christoph Koentges ,&nbsp;Elisabeth Khan ,&nbsp;Katharina Pfeil ,&nbsp;Robert Sandulescu ,&nbsp;Sayan Bakshi ,&nbsp;Carolin Költgen ,&nbsp;Ivan Vosko ,&nbsp;Johannes Gollmer ,&nbsp;Thomas Rathner ,&nbsp;Günter Roth ,&nbsp;Michael M. Hoffmann ,&nbsp;Katja E. Odening ,&nbsp;Hauke Horstmann ,&nbsp;Luke A. Potter ,&nbsp;Christoph Bode ,&nbsp;Dennis Wolf ,&nbsp;Harald Sourij ,&nbsp;Senka Ljubojevic-Holzer ,&nbsp;Markus Wallner ,&nbsp;Heiko Bugger","doi":"10.1016/j.jmccpl.2025.100299","DOIUrl":"10.1016/j.jmccpl.2025.100299","url":null,"abstract":"<div><h3>Aims</h3><div>Sirtuin 4 (SIRT4) is a mitochondrially-localized stress-responsive NAD⁺-dependent deacetylase predominantly regulating energy metabolism and reactive oxygen species (ROS) homeostasis. Overexpression of SIRT4 aggravates angiotensin-induced cardiac hypertrophy, however underlying mechanisms remain incompletely elucidated. To current study was designed to explore mechanisms underlying adverse effects of increased SIRT4 levels in the heart following pressure overload.</div></div><div><h3>Methods and results</h3><div>Mice with cardiomyocyte-specific overexpression of <em>Sirt4</em> (c<em>Sirt4</em>-Tg) or non-transgenic controls underwent transverse aortic constriction (TAC) or sham procedure. Cardiac structure, function and energy metabolism were assessed by echocardiography and working heart perfusions. Transcriptome analysis was performed using RNA sequencing. Nine weeks following TAC and thereafter, c<em>Sirt4</em>-Tg mice displayed exacerbated cardiac dilation, dysfunction, and fibrosis compared to non-transgenic controls. This aggravation was accompanied by impaired rates of glycolysis and a blunted increase of mitochondrial respiratory capacity. More importantly, expression of numerous genes encoding collagens and profibrotic regulators was elevated. This profibrotic signaling was reversed by mitochondria-targeted antioxidant treatment using MitoQ, along with attenuation of cardiac dysfunction and reversal of structural remodeling. SIRT4 may drive oxidative stress and fibrotic signaling via increased NOX4 expression (&gt;7-fold), and/or direct modulation of potential SIRT4 targets newly identified by Human Protein Microarray, including calcitonin gene-related peptide receptor component protein, cyclophilin A, and interleukin-2 receptor β.</div></div><div><h3>Conclusions</h3><div><em>SIRT4</em> overexpression accelerates heart failure development in response to pressure overload, predominantly by ROS-mediated enhancement of profibrotic transcriptional signaling.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100299"},"PeriodicalIF":0.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927428","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":"PP2A-B56α is a key determinant of cardiac protein phosphorylation and functional responses to β-adrenergic signalling","authors":"Alican Güran ,&nbsp;Yanlong Ji ,&nbsp;Pan Fang ,&nbsp;Kuan-Ting Pan ,&nbsp;Henning Urlaub ,&nbsp;Metin Avkiran ,&nbsp;Christof Lenz ,&nbsp;Kate L. Weeks","doi":"10.1016/j.jmccpl.2025.100301","DOIUrl":"10.1016/j.jmccpl.2025.100301","url":null,"abstract":"<div><div>B56α is a protein phosphatase 2 A (PP2A) regulatory subunit which modulates the heart's inotropic response to acute β-adrenergic receptor (β-AR) stimulation, although knowledge of the underlying molecular mechanisms is limited. In this study, mice deficient for B56α and wildtype controls received an intraperitoneal injection of isoproterenol (0.1 mg/kg) to activate β-AR signalling <em>in vivo</em>, and their hearts examined two minutes post-injection by quantitative phosphoproteomics to identify mechanisms of acute β-adrenergic signalling. We identified site- and genotype-specific phosphorylation changes on &gt;200 proteins, including 25 hyperphosphorylated proteins harbouring a B56 binding motif as putative substrates. Functional enrichment analysis pointed to cardiac Ca²⁺ release and contractility as key processes impacted by B56α deficiency, as well as cardiac muscle hypertrophy as a potential disease mechanism. In vitro, loss of B56α in cardiomyocytes blunted acute isoproterenol-induced increases in intracellular calcium transient amplitude, confirming that B56α plays a key role in calcium handling. In vivo, loss of B56α protected mice from developing systolic dysfunction in response to sustained isoproterenol infusion (60 mg/kg/day for 14 days), despite comparable increases in heart mass. These findings reaffirm a key role for B56α as a mediator of physiologically important cardiac responses to β-AR stimulation and reveal potential new molecular mechanisms for this regulatory function, including putative cardiac B56α substrates.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100301"},"PeriodicalIF":0.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948223","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":"Low levels of adropin are associated with acute kidney injury after decongestion in patients with acutely decompensated heart failure","authors":"Alexander E. Berezin ,&nbsp;Tetiana A. Berezina ,&nbsp;Evgen V. Novikov ,&nbsp;Oleksandr O. Berezin","doi":"10.1016/j.jmccpl.2025.100302","DOIUrl":"10.1016/j.jmccpl.2025.100302","url":null,"abstract":"<div><h3>Background</h3><div>Patients with acutely decompensated heart failure (ADHF) demonstrated a high risk of acute kidney injury (AKI) and its transition to acute kidney disease after diuretic therapy to reach euvolemic status. The purpose of the study was to investigate whether circulating levels of adropin predict AKI in ADHF patients after decongestive therapy.</div></div><div><h3>Material and methods</h3><div>A total of 325 individuals fulfilling the inclusion criteria of ADHF were consecutively enrolled from October 2020 to October 2024. The study was designed as prospective cohort study. The congestion was assessed using Framingham criteria of congestion (Framingham heart failure score ≥ 2). Patients with AHDF were divided into 2 groups according to the presence of AKI (<em>n</em> = 113) and without AKI (<em>n</em> = 212). Circulating levels of N-terminal brain natriuretic pro-peptide (NT-proBNP), high-sensitivity C-reactive protein, high-sensitive troponin T, interleukin-6, tumor necrosis factor-alpha, soluble suppression of tumorigenicity-2, procalcitonin were measured. Predictors of AKI were identified using univariate and multivariate logistic regression analysis.</div></div><div><h3>Results</h3><div>We found that the presence of atrial fibrillation, urinary albumin/creatinine ratio (UACR) ≥16.5 mg/g Cr, serum levels of adropin&lt;2.1 ng/mL and NT-proBNP ≥19,540 pmol/mL were independent predictors for AKI in patients with ADHF. UACR and atrial fibrillation revealed a strict similarity in prediction of AKI, whereas discriminative ability of adropin&lt;2.1 ng/mL were higher to NT-proBNP ≥19,540 pmol/mL. The combined predictive model (low levels of adropin + higher levels of NT-proBNP) showed significantly better discriminatory power compared to other models.</div></div><div><h3>Conclusion</h3><div>Low levels of adropin&lt;2.1 ng/mL on hospital admission in patients with ADHF can predict AKI and that its predictive ability was significantly higher compared with the conventionally used urinary albumin/creatinine ratio and NT-proBNP. Adropin may add predictive information to NT-proBNP for AKI in individuals with ADHF.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100302"},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899749","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":"Independent and synergistic roles of MEK-ERK1/2 and PKC pathways in regulating functional changes in vascular tissue following flow cessation","authors":"Spyridoula Kazantzi ,&nbsp;Lars Edvinsson ,&nbsp;Kristian Agmund Haanes","doi":"10.1016/j.jmccpl.2025.100300","DOIUrl":"10.1016/j.jmccpl.2025.100300","url":null,"abstract":"<div><h3>Background</h3><div>The MEK-ERK1/2 and PKC pathways play critical roles in regulating functional changes in tissues, but their interplay remains poorly understood. The vasculature provides an ideal model to study these pathways, particularly under conditions of flow cessation, which is highly relevant to ischemia and other cardiovascular diseases. This study examined the independent roles, additive effects, and time-dependent dynamics of MEK and PKC pathway inhibition in functional receptor upregulation.</div></div><div><h3>Methods</h3><div>Rat basilar arteries were cultured for 48 h with selective inhibitors targeting MEK (Trametinib), PKC (RO-317549) and their downstream ERK (Ulixertinib) and NF-kB (BMS 345541). Functional changes in ET_B receptor responses were assessed via wire myography following stimulation with Sarafotoxin 6c (S6c). Western blot analysis quantified ERK phosphorylation, and the effects of inhibitor timing and combination treatments were evaluated.</div></div><div><h3>Results</h3><div>MEK inhibition reduced ERK phosphorylation and ET_B receptor-mediated contractility, whereas PKC inhibition had no effect on ERK phosphorylation but significantly reduced ET_B receptor function. Combining MEK and PKC inhibitors produced an additive effect, resulting in greater suppression of functional changes compared to single treatments. At 6 h following flow cessation, PKC inhibition effectively suppressed ET_B receptor function, while MEK inhibition had minimal effects when introduced at this delayed time point.</div></div><div><h3>Conclusions</h3><div>The MEK and PKC pathways independently drive functional changes in vascular tissue, particularly following flow cessation. MEK inhibition is effective early, while PKC inhibition remains effective when applied later. The additive effects observed with combined MEK and PKC inhibition indicate parallel and functionally independent pathway activation during ET_B receptor upregulation.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100300"},"PeriodicalIF":0.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895852","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}