Journal of molecular and cellular cardiology plus最新文献

{"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}

{"title":"Right ventricle remodelling: from in vitro to in vivo and from simple to complex models","authors":"Paula A. da Costa Martins ,&nbsp;Martina Calore ,&nbsp;Jordy M.M. Kocken","doi":"10.1016/j.jmccpl.2025.100298","DOIUrl":"10.1016/j.jmccpl.2025.100298","url":null,"abstract":"<div><div>Right ventricle failure (RVF) is a debilitating disease with no cure available. While much is known about the failing left ventricle (LV), many mechanisms and signalling pathways of remodelling are different between the two ventricles. Over the past decades, new insights into the mechanisms of the disease have helped in managing disease progression and improving patient comfort. To study RVF both <em>in vitro</em> and <em>in vivo</em> and even <em>ex vivo</em>, relevant experimental models are required to discover new mechanisms and test novel therapeutic approaches. During the past decades many strategies to mimick RV hypertrophy (RVH), to some extent, have been developed and described with using varying methods of disease induction. Such models either require genetic modulation, surgical intervention, chemical injections, or changes in environmental exposure.</div><div>As each approach has a different set of requirements of facility and skills, one needs to carefully consider which one better suits a specific study or answer a specific research question. In this review, we provide an overview of the most common <em>in vitro</em> techniques, both 2 and 3 dimensional, <em>in vivo</em> and promising <em>ex vivo</em> approaches to study RV remodelling.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100298"},"PeriodicalIF":0.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833656","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":"SGLT2 inhibitor upregulates myocardial genes for oxidative phosphorylation and fatty acid metabolism in Gαq-mice","authors":"Jordan M. Chambers,&nbsp;Dominique Croteau,&nbsp;David R. Pimentel,&nbsp;Adam C. Gower,&nbsp;Marcello Panagia,&nbsp;Tomas Baka,&nbsp;Fuzhong Qin,&nbsp;Ivan Luptak,&nbsp;Wilson S. Colucci","doi":"10.1016/j.jmccpl.2025.100296","DOIUrl":"10.1016/j.jmccpl.2025.100296","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial dysfunction with decreased ATP production and increased release of reactive oxygen species (ROS) is a hallmark of the failing heart. Although SGLT2 inhibitors have been shown to improve myocardial metabolism in the failing heart, independent of diabetes, the effect on mitochondria is not clear.</div></div><div><h3>Objectives</h3><div>Our goal was to test the effect of the SGLT2 inhibitor ertugliflozin on mitochondrial gene expression and function in myocardium and isolated mitochondria from non-diabetic mice with dilated cardiomyopathy due to cardiac-specific over-expression of Gαq.</div></div><div><h3>Methods</h3><div>Gαq and wild type (WT) littermates 4 weeks of age were treated for 16 weeks with or without the SGLT2 inhibitor ertugliflozin (ERTU) formulated in the chow (0.5 mg/g chow).</div></div><div><h3>Results</h3><div>From weeks 4 to 20, Gαq mice developed progressive cardiac hypertrophy, dilation, contractile dysfunction, myocyte apoptosis and interstitial fibrosis – all of which were prevented by ERTU treatment. Isolated cardiac mitochondria from Gαq mice had decreased maximal ATP production and increased ROS release - both of which were normalized by ERTU. In isolated beating hearts from Gαq mice, contractile reserve and high energy phosphates measured simultaneously by ³¹P NMR spectroscopy were decreased - and both were improved by ERTU. In Gαq mice, marked suppression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism was reversed by ERTU.</div></div><div><h3>Conclusions</h3><div>The SGLT2 inhibitor ERTU corrected the expression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism, and was associated with increased production of ATP, decreased release of mitochondrial ROS, and amelioration of the consequences of mitochondrial dysfunction on myocardial structure and function.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100296"},"PeriodicalIF":0.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143830186","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":"Matured hiPSC-derived cardiomyocytes possess dematuration plasticity","authors":"Fang Meng ,&nbsp;Maxwell Kwok ,&nbsp;Yen Chin Hui ,&nbsp;Ruofan Wei ,&nbsp;Alejandro Hidalgo-Gonzalez ,&nbsp;Anna Walentinsson ,&nbsp;Henrik Andersson ,&nbsp;Frederik Adam Bjerre ,&nbsp;Qing-Dong Wang ,&nbsp;Ditte C. Andersen ,&nbsp;Ellen Ngar-Yun Poon ,&nbsp;Daniela Später ,&nbsp;David C. Zebrowski","doi":"10.1016/j.jmccpl.2025.100295","DOIUrl":"10.1016/j.jmccpl.2025.100295","url":null,"abstract":"<div><div>Human induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used to identify potential factors capable of inducing endogenous cardiomyocyte proliferation to regenerate the injured heart. L-type calcium channel blockers have previously been identified as a class of factors capable of inducing matured hiPSC-CMs to proliferate. However, the mechanism by which L-type calcium channel blockers promote hiPSC-CM proliferation remains unclear. Here we provide evidence that matured hiPSC-CMs possess plasticity to undergo dematuration in response to certain pharmacological compounds. Consistent with primary cardiomyocyte maturation during perinatal development, we found that centrosome disassembly occurs in hiPSC-CMs during plate-based, temporal, maturation. A small molecule screen identified nitrendipine, an L-type calcium channel blocker, and 1-NA-PP1, a Src kinase inhibitor, as factors capable of inducing centrosome reassembly in a subpopulation of hiPSC-CMs. Furthermore, centrosome-positive hiPSC-CMs were more likely to exhibit cell cycle activity than centrosome-negative hiPSC-CMs. In contrast, neither nitrendipine or 1-NA-PP1 induced centrosome reassembly, or cell cycle activity, in neonatal rat ventricular myocytes (NRVMs). Differential bulk transcriptome analysis indicated that matured hiPSC-CMs, but not NRVMs, treated with nitrendipine or 1-NA-PP1 undergo dematuration. ScRNA transcriptome analysis supported that matured hiPSC-CMs treated with either nitrendipine or 1-NA-PP1 undergo dematuration. Collectively, our results indicate that matured hiPSC-CMs, but not primary NRVMs, possess plasticity to undergo dematuration in response to certain pharmacological compounds such as L-type calcium channel blockers and Src-kinase inhibitors. This study shows that once mature, hiPSC-CMs may not maintain their maturity under experimental conditions which may have implications for experimental systems where the state of hiPSC-CM maturation is relevant.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100295"},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791390","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":"Targeting the CD39/CD73 pathway: New insights into cardiac fibrosis and inflammation in female cardiac surgery patients","authors":"Eitezaz Mahmood ,&nbsp;Mark Robitaille ,&nbsp;Yifan Bu ,&nbsp;Adnan Khan ,&nbsp;Marie-France Poulin ,&nbsp;Feroze Mahmood ,&nbsp;Ruma Bose ,&nbsp;Kamal R. Khabbaz ,&nbsp;Simon C. Robson ,&nbsp;Robina Matyal","doi":"10.1016/j.jmccpl.2025.100294","DOIUrl":"10.1016/j.jmccpl.2025.100294","url":null,"abstract":"<div><div>Women undergoing cardiac surgery suffer from worse outcomes than their male counterparts. The reasons for this disparity are multifactorial, but the loss of the protective effects of estrogen likely plays a role. Estrogen acts on the CD39/CD73 purine pathway, and loss of estrogen effects may contribute to the increased inflammation seen in post-menopausal women. We aimed to compare CD39/CD73 expression and downstream fibrosis, and inflammation in men and women undergoing cardiac surgery and then used an ovariectomy/high fat diet mouse model to approximate women who present for cardiac surgery to test therapeutics. We found decreased CD39 and CD73 in women compared to men, which was associated with increased fibrosis. Apyrase supplementation (a CD39 mimetic) improved ejection fraction and decreased E/e’. Increased CD73 function (via dipyridamole) decreased fibrosis. This study demonstrates the importance of purinergic dysfunction in cardiovascular disease in women and presents two potential therapeutics to improve cardiac health via manipulation of purine pathways.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100294"},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726112","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":"Electrophysiological comparison of left versus right stellate ganglia neurons","authors":"Arie O. Verkerk ,&nbsp;Carol Ann Remme ,&nbsp;Molly O'Reilly","doi":"10.1016/j.jmccpl.2025.100293","DOIUrl":"10.1016/j.jmccpl.2025.100293","url":null,"abstract":"<div><h3>Background</h3><div>The stellate ganglia of the peripheral autonomic nervous system innervate the heart and continuously fine-tune cardiac function to meet physiological demands. The right stellate ganglion (RSG) predominantly innervates the sinoatrial node and has functional effects on chronotropy/heart rate, whereas the left stellate ganglion (LSG) has predominance in the ventricular myocardium and impacts inotropy/contractility. Whilst the innervation patterns and functional consequences of block and stimulation are well-documented, basic electrophysiological characterisation and single-cell comparison of RSG and LSG neurons has not been performed. In addition, sex differences in stellate ganglion action potential (AP) parameters may exist, but remain as yet unknown.</div></div><div><h3>Methods/results</h3><div>Here we characterise the electrical properties of enzymatically isolated mouse stellate ganglia neurons using the patch clamp technique. Using 500 ms depolarising pulses of varying amplitude, we provide detailed characterisation of basic AP properties and their correlations. We reveal that there are two populations of neurons in terms of their AP firing properties (phasic or tonic firing), with the majority (65 %) firing with a phasic pattern. When all recordings were pooled, tonic neurons had a significantly larger AP amplitude (85 ± 3.0 vs 76 ± 2.4 mV) and overshoot (28 ± 1.8 vs 19 ± 1.8 mV) compared to phasic neurons (<em>P</em> &lt; 0.05). Moreover, phasic neurons did not fire spontaneously, whereas 50 % of tonic neurons did, and more often presented with anodal break excitation (<em>P</em> &lt; 0.05). When male vs female neurons were compared (with LSG and RSG neurons as subgroups), males had a more negative minimum diastolic potential (MDP; −55 ± 1.7 vs −47 ± 3.0 mV, <em>P</em> &lt; 0.05) and higher percentage of anodal break excitation (<em>P</em> ≤ 0.05). When LSG vs RSG neurons were compared (with gender as subgroups), no significant differences were observed except a higher percentage of anodal break excitation in the RSG (<em>P</em> ≤ 0.05).</div></div><div><h3>Conclusions</h3><div>Isolated RSG and LSG neurons have similar AP firing patterns and properties. A significant difference was observed in the MDP and anodal break excitation of male vs female neurons. However, all other AP parameters were similar. This suggests that the LSG and RSG can be combined irrespective of sex when investigating the electrophysiological properties of these distinct anatomical structures.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"12 ","pages":"Article 100293"},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696710","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":"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}