Journal of molecular and cellular cardiology最新文献

{"title":"Arrhythmogenic cardiomyopathy-related cadherin variants affect desmosomal binding kinetics","authors":"Manuel Göz ,&nbsp;Greta Pohl ,&nbsp;Sylvia M. Steinecker ,&nbsp;Volker Walhorn ,&nbsp;Hendrik Milting ,&nbsp;Dario Anselmetti","doi":"10.1016/j.yjmcc.2024.07.009","DOIUrl":"10.1016/j.yjmcc.2024.07.009","url":null,"abstract":"<div><p>Cadherins are calcium dependent adhesion proteins that establish and maintain the intercellular mechanical contact by bridging the gap between adjacent cells. Desmoglein-2 (Dsg2) and desmocollin-2 (Dsc2) are tissue specific cadherin isoforms of the cell-cell contact in cardiac desmosomes. Mutations in the <em>DSG2</em>-gene and in the <em>DSC2</em>-gene are related to arrhythmogenic right ventricular cardiomyopathy (ARVC) a rare but severe heart muscle disease. Here, several possible homophilic and heterophilic binding interactions of wild-type Dsg2, wild-type Dsc2, as well as one Dsg2- and two Dsc2-variants, each associated with ARVC, are investigated. Using single molecule force spectroscopy (SMFS) with atomic force microscopy (AFM) and applying Jarzynski's equality the kinetics and thermodynamics of Dsg2/Dsc2 interaction can be determined. The free energy landscape of Dsg2/Dsc2 dimerization exposes a high activation energy barrier, which is in line with the proposed strand-swapping binding motif. Although the binding motif is not affected by any of the mutations, the binding kinetics of the interactions differ significantly from the wild-type. While wild-type cadherins exhibit an average complex lifetime of approx. 0.3 s interactions involving a variant consistently show - lifetimes that are substantially larger. The lifetimes of the wild-type interactions give rise to the picture of a dynamic adhesion interface consisting of continuously dissociating and (re)associating molecular bonds, while the delayed binding kinetics of interactions involving an ARVC-associated variant might be part of the pathogenesis. Our data provide a comprehensive and consistent thermodynamic and kinetic description of cardiac cadherin binding, allowing detailed insight into the molecular mechanisms of cell adhesion.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"195 ","pages":"Pages 36-44"},"PeriodicalIF":4.9,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824001251/pdfft?md5=ddd7c4601e26596aa4cb66c3774559d7&pid=1-s2.0-S0022282824001251-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141844644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The W792R HCM missense mutation in the C6 domain of cardiac myosin binding protein-C increases contractility in neonatal mouse myocardium","authors":"Jasmine Mertens ,&nbsp;Willem J. De Lange ,&nbsp;Emily T. Farrell ,&nbsp;Ella C. Harbaugh ,&nbsp;Angeela Gauchan ,&nbsp;Daniel P. Fitzsimons ,&nbsp;Richard L. Moss ,&nbsp;J. Carter Ralphe","doi":"10.1016/j.yjmcc.2024.07.007","DOIUrl":"10.1016/j.yjmcc.2024.07.007","url":null,"abstract":"<div><p>Missense mutations in cardiac myosin binding protein C (cMyBP-C) are known to cause hypertrophic cardiomyopathy (HCM). The W792R mutation in the C6 domain of cMyBP-C causes severe, early onset HCM in humans, yet its impact on the function of cMyBP-C and the mechanism through which it causes disease remain unknown. To fully characterize the effect of the W792R mutation on cardiac morphology and function in vivo, we generated a murine knock-in model<em>.</em> We crossed heterozygous W792R^WR mice to produce homozygous mutant W792R^RR, heterozygous W792R^WR_, and control W792R^WW mice. W792R^RR mice present with cardiac hypertrophy, myofibrillar disarray and fibrosis by postnatal day 10 (PND10), and do not survive past PND21. Full-length cMyBP-C is present at similar levels in W792R^WW, W792R^WR and W792R^RR mice and is properly incorporated into the sarcomere. Heterozygous W792R^WR mice displayed normal heart morphology and contractility. Permeabilized myocardium from PND10 W792R^RR mice showed increased Ca²⁺ sensitivity, accelerated cross-bridge cycling kinetics, decreased cooperativity in the activation of force, and increased expression of hypertrophy-related genes. In silico modeling suggests that the W792R mutation destabilizes the fold of the C6 domain and increases torsion in the C5-C7 region, possibly impacting regulatory interactions of cMyBP-C with myosin and actin. Based on the data presented here, we propose a model in which mutant W792R cMyBP-C preferentially forms Ca²⁺ sensitizing interactions with actin, rather than inhibitory interactions with myosin. The W792R-cMyBP-C mouse model provides mechanistic insights into the pathology of this mutation and may provide a mechanism by which other central domain missense mutations in cMyBP-C may alter contractility, leading to HCM.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"195 ","pages":"Pages 14-23"},"PeriodicalIF":4.9,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ryanodine receptor stabilization therapy suppresses Ca2+- based arrhythmias in a novel model of metabolic HFpEF","authors":"Aaron D. Kaplan ,&nbsp;Liron Boyman ,&nbsp;Christopher W. Ward ,&nbsp;W. Jonathan Lederer ,&nbsp;Maura Greiser","doi":"10.1016/j.yjmcc.2024.07.006","DOIUrl":"10.1016/j.yjmcc.2024.07.006","url":null,"abstract":"<div><p>Heart Failure with preserved ejection fraction (HFpEF) has a high rate of sudden cardiac death (SCD) and empirical treatment is ineffective. We developed a novel preclinical model of metabolic HFpEF that presents with stress-induced ventricular tachycardia (VT). Mechanistically, we discovered arrhythmogenic changes in intracellular Ca²⁺ handling distinct from the changes pathognomonic for heart failure with reduced ejection fraction. We further show that dantrolene, a stabilizer of the ryanodine receptor Ca²⁺ channel, attenuates HFpEF-associated arrhythmogenic Ca²⁺ handling <em>in vitro</em> and suppresses stress<em>-</em>induced VT <em>in vivo</em>. We propose ryanodine receptor stabilization as a mechanistic approach to mitigation of malignant VT in metabolic HFpEF.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"195 ","pages":"Pages 68-72"},"PeriodicalIF":4.9,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824001226/pdfft?md5=9d6a1f3a7c8870076c1bfc36db23a01e&pid=1-s2.0-S0022282824001226-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient formation of collaterals contributes to the restoration of the arterial tree during cardiac regeneration in neonatal mice","authors":"Rachel Sturny,&nbsp;Lucie Boulgakoff,&nbsp;Robert G. Kelly,&nbsp;Lucile Miquerol","doi":"10.1016/j.yjmcc.2024.07.005","DOIUrl":"10.1016/j.yjmcc.2024.07.005","url":null,"abstract":"<div><p>Revascularization of ischemic myocardium following cardiac damage is an important step in cardiac regeneration. However, the mechanism of arteriogenesis has not been well described during cardiac regeneration. Here we investigated coronary artery remodeling and collateral growth during cardiac regeneration. Neonatal MI was induced by ligature of the left descending artery (LAD) in postnatal day (P) 1 or P7 pups from the <em>Cx40-GFP</em> mouse line and the arterial tree was reconstructed in 3D from images of cleared hearts collected at 1, 2, 4, 7 and 14 days after infarction. We show a rapid remodeling of the left coronary arterial tree induced by neonatal MI and the formation of numerous collateral arteries, which are transient in regenerating hearts after MI at P1 and persistent in non-regenerating hearts after MI at P7. This difference is accompanied by restoration of a perfused or a non-perfused LAD following MI at P1 or P7 respectively. Interestingly, collaterals ameliorate cardiac perfusion and drive LAD repair, and lineage tracing analysis demonstrates that the restoration of the LAD occurs by remodeling of pre-existing arterial cells independently of whether they originate in large arteries or arterioles. These results demonstrate that the restoration of the LAD artery during cardiac regeneration occurs by pruning as the rapidly forming collaterals that support perfusion of the disconnected lower LAD subsequently disappear on restoration of a unique LAD. These results highlight a rapid phase of arterial remodeling that plays an important role in vascular repair during cardiac regeneration.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"195 ","pages":"Pages 1-13"},"PeriodicalIF":4.9,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelin-1 influences mechanical properties and contractility of hiPSC derived cardiomyocytes resulting in diastolic dysfunction","authors":"Caterina Redwanz ,&nbsp;Ricardo H. Pires ,&nbsp;Doreen Biedenweg ,&nbsp;Stefan Groß ,&nbsp;Oliver Otto ,&nbsp;Stephanie Könemann","doi":"10.1016/j.yjmcc.2024.07.004","DOIUrl":"10.1016/j.yjmcc.2024.07.004","url":null,"abstract":"<div><p>A better understanding of the underlying pathomechanisms of diastolic dysfunction is crucial for the development of targeted therapeutic options with the aim to increase the patients' quality of life. In order to shed light on the processes involved, suitable models are required. Here, effects of endothelin-1 (ET-1) treatment on cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) were investigated. While it is well established, that ET-1 treatment induces hypertrophy in cardiomyocytes, resulting changes in cell mechanics and contractile behavior with focus on relaxation have not been examined before. Cardiomyocytes were treated with 10 nM of ET-1 for 24 h and 48 h, respectively. Hypertrophy was confirmed by real-time deformability cytometry (RT-DC) which was also used to assess the mechanical properties of cardiomyocytes. For investigation of the contractile behavior, 24 h phase contrast video microscopy was applied. To get a deeper insight into changes on the molecular biological level, gene expression analysis was performed using the NanoString nCounter® cardiovascular disease panel. Besides an increased cell size, ET-1 treated cardiomyocytes are stiffer and show an impaired relaxation. Gene expression patterns in ET-1 treated hiPSC derived cardiomyocytes showed that pathways associated with cardiovascular diseases, cardiac hypertrophy and extracellular matrix were upregulated while those associated with fatty acid metabolism were downregulated. We conclude that alterations in cardiomyocytes after ET-1 treatment go far beyond hypertrophy and represent a useful model for diastolic dysfunction.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"194 ","pages":"Pages 105-117"},"PeriodicalIF":4.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824001184/pdfft?md5=a49d2c318127024240184c8ba386620a&pid=1-s2.0-S0022282824001184-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc attenuates monocrotaline-induced pulmonary hypertension in rats through upregulation of A20","authors":"Weixiao Chen ,&nbsp;Ai Chen ,&nbsp;Guili Lian ,&nbsp;Yan Yan ,&nbsp;Junping Liu ,&nbsp;Jingying Wu ,&nbsp;Gufeng Gao ,&nbsp;Liangdi Xie","doi":"10.1016/j.yjmcc.2024.07.003","DOIUrl":"10.1016/j.yjmcc.2024.07.003","url":null,"abstract":"<div><p>Pulmonary hypertension (PH) is characterized by excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), in which inflammatory signaling caused by activation of the NF-κB pathway plays an important role. A20 is an important negative regulator of the NF-κB pathway, and zinc promotes the expression of A20 and exerts a protective effect against various diseases (<em>e.g.</em> COVID19) by inhibiting the inflammatory signaling. The role of A20 and intracellular zinc signaling in PH has been explored, but the extracellular zinc signaling is not well understood, and whether zinc has protective effects on PH is still elusive. Using inductively coupled plasma mass spectrometry (ICP-MS), we studied the alteration of trace elements during the progression of monocrotaline (MCT)-induced PH and found that serum zinc concentration was decreased with the onset of PH accompanied by abnormalities of other three elements, including copper, chromium, and magnesium. Zinc chloride injection with the dosage of 5 mg/kg intraperitoneally partially corrected this abnormality and inhibited the progression of PH. Zinc supplementation induced the expression of A20 in lung tissue and reduce the inflammatory responses. <em>In vitro</em>, zinc supplementation time-dependently upregulated the expression of A20 in PASMCs, therefore correcting the excessive proliferation and migration of cells caused by hypoxia. Using genetically encoded-FRET based zinc probe, we found that these effects of zinc ions are not achieved by entering cells, but most likely by activating cell surface zinc receptor (ZnR/GPR39). These results provide the first evidence of the effectiveness of zinc supplementation in the treatment of PH.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"195 ","pages":"Pages 24-35"},"PeriodicalIF":4.9,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824001111/pdfft?md5=e61a374a3addf73b732b912c926ce55c&pid=1-s2.0-S0022282824001111-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired balance between coronary blood flow and myocardial metabolism in postpartum swine","authors":"Selina M. Tucker ,&nbsp;Salman I. Essajee ,&nbsp;Cooper M. Warne ,&nbsp;Gregory M. Dick ,&nbsp;Michael P. Heard ,&nbsp;Nicole Crowe ,&nbsp;Styliani Goulopoulou ,&nbsp;Johnathan D. Tune","doi":"10.1016/j.yjmcc.2024.07.002","DOIUrl":"10.1016/j.yjmcc.2024.07.002","url":null,"abstract":"<div><p>Understanding of the mechanisms contributing to the increased maternal susceptibility for major adverse cardiovascular events in the postpartum period remains poor. Accordingly, this study tested the hypothesis that the balance between coronary blood flow and myocardial metabolism is compromised during the puerperium period (35–45 days post-delivery) in swine. Systemic and coronary hemodynamic responses were assessed in anesthetized, open-chest control (nonpregnant) and puerperium/postpartum swine at baseline and in response to intravenous infusion of dobutamine (1–30 μg/kg/min). Blood pressure and heart rate were lower in postpartum swine at baseline and in response to dobutamine (<em>P</em> &lt; 0.05). Coronary blood flow and myocardial oxygen delivery were significantly diminished at baseline in postpartum swine (<em>P</em> &lt; 0.001), which corresponded with ∼35% reduction in myocardial oxygen consumption (MVO₂) (P &lt; 0.001). Postpartum swine displayed enhanced retrograde coronary flow, larger cardiomyocyte area (<em>P</em> &lt; 0.01) and marked capillary rarefaction (P &lt; 0.01). The relationship between coronary blood flow and heart rate (<em>P</em> &lt; 0.05) or MVO₂ (<em>P</em> &lt; 0.001) was significantly diminished in postpartum swine as dobutamine increased MVO₂ up to ∼135% in both groups. This reduction in myocardial perfusion was associated with decreases in myocardial lactate uptake (<em>P</em> &lt; 0.001), increases in coronary venous PCO₂ (<em>P</em> &lt; 0.01) and decreased coronary venous pH (P &lt; 0.01). These findings suggest an impaired balance between coronary blood flow and myocardial metabolism could contribute to the increased incidence of maternal myocardial ischemia and premature death in the postpartum period.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"194 ","pages":"Pages 96-104"},"PeriodicalIF":4.9,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional coactivation of NRF2 signaling in cardiac fibroblasts promotes resistance to oxidative stress","authors":"Lisa K. McClendon,&nbsp;Rainer B. Lanz,&nbsp;Anil Panigrahi,&nbsp;Kristan Gomez,&nbsp;Michael J. Bolt,&nbsp;Min Liu,&nbsp;Fabio Stossi,&nbsp;Michael A. Mancini,&nbsp;Clifford C. Dacso,&nbsp;David M. Lonard,&nbsp;Bert W. O'Malley","doi":"10.1016/j.yjmcc.2024.07.001","DOIUrl":"10.1016/j.yjmcc.2024.07.001","url":null,"abstract":"<div><p>We recently discovered that steroid receptor coactivators (SRCs) SRCs-1, 2 and 3, are abundantly expressed in cardiac fibroblasts (CFs) and their activation with the SRC small molecule stimulator MCB-613 improves cardiac function and dramatically lowers pro-fibrotic signaling in CFs post-myocardial infarction. These findings suggest that CF-derived SRC activation could be beneficial in the mitigation of chronic heart failure after ischemic insult. However, the cardioprotective mechanisms by which CFs contribute to cardiac pathological remodeling are unclear. Here we present studies designed to identify the molecular and cellular circuitry that governs the anti-fibrotic effects of an MCB-613 derivative, MCB-613-10-1, in CFs. We performed cytokine profiling and whole transcriptome and proteome analyses of CF-derived signals in response to MCB-613-10-1. We identified the NRF2 pathway as a direct MCB-613-10-1 therapeutic target for promoting resistance to oxidative stress in CFs. We show that MCB-613-10-1 promotes cell survival of anti-fibrotic CFs exposed to oxidative stress by suppressing apoptosis. We demonstrate that an increase in HMOX1 expression contributes to CF resistance to oxidative stress-mediated apoptosis via a mechanism involving SRC co-activation of NRF2, hence reducing inflammation and fibrosis. We provide evidence that MCB-613-10-1 acts as a protectant against oxidative stress-induced mitochondrial damage. Our data reveal that SRC stimulation of the NRF2 transcriptional network promotes resistance to oxidative stress and highlights a mechanistic approach toward addressing pathologic cardiac remodeling.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"194 ","pages":"Pages 70-84"},"PeriodicalIF":4.9,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824001093/pdfft?md5=4d1b198b0dc7feedf1b3bbea77ded909&pid=1-s2.0-S0022282824001093-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting calpain-2-mediated junctophilin-2 cleavage delays heart failure progression following myocardial infarction","authors":"Satadru K. Lahiri ,&nbsp;Jiao Lu ,&nbsp;Yuriana Aguilar-Sanchez ,&nbsp;Hui Li ,&nbsp;Lucia M. Moreira ,&nbsp;Mohit M. Hulsurkar ,&nbsp;Arielys Mendoza ,&nbsp;Mara R. Turkieltaub Paredes ,&nbsp;Jose Alberto Navarro-Garcia ,&nbsp;Elda Munivez ,&nbsp;Brooke Horist ,&nbsp;Oliver M. Moore ,&nbsp;Gunnar Weninger ,&nbsp;Sören Brandenburg ,&nbsp;Christof Lenz ,&nbsp;Stephan E. Lehnart ,&nbsp;Rana Sayeed ,&nbsp;George Krasopoulos ,&nbsp;Vivek Srivastava ,&nbsp;Lilei Zhang ,&nbsp;Xander H.T. Wehrens","doi":"10.1016/j.yjmcc.2024.06.011","DOIUrl":"10.1016/j.yjmcc.2024.06.011","url":null,"abstract":"<div><p>Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created a novel knock-in mouse model by removing residues 479-SPAGTPPQ-486 to prevent calpain-2-mediated cleavage at this site. Functional and molecular assessment of cardiac function post-MI in cleavage site deletion (CSD) mice showed preserved cardiac contractility and reduced dilation, reduced JPH2-CTP levels, attenuated adverse remodeling, improved T-tubular structure, and normalized SR Ca²⁺-handling. Adenovirus mediated calpain-2 knockdown in mice exhibited similar findings. Pulldown of CTP followed by proteomic analysis revealed valosin-containing protein (VCP) and BAG family molecular chaperone regulator 3 (BAG3) as novel binding partners of JPH2. Together, our findings suggest that blocking calpain-2-mediated JPH2 cleavage may be a promising new strategy for delaying the development of HF following MI.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"194 ","pages":"Pages 85-95"},"PeriodicalIF":4.9,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional consequences of changes in the distribution of Ca2+ extrusion pathways between t-tubular and surface membranes in a model of human ventricular cardiomyocyte","authors":"Michal Pásek ,&nbsp;Markéta Bébarová ,&nbsp;Milena Šimurdová ,&nbsp;Jiří Šimurda","doi":"10.1016/j.yjmcc.2024.06.010","DOIUrl":"10.1016/j.yjmcc.2024.06.010","url":null,"abstract":"<div><p>The sarcolemmal Ca²⁺ efflux pathways, Na⁺-Ca²⁺-exchanger (NCX) and Ca²⁺-ATPase (PMCA), play a crucial role in the regulation of intracellular Ca²⁺ load and Ca²⁺ transient in cardiomyocytes. The distribution of these pathways between the t-tubular and surface membrane of ventricular cardiomyocytes varies between species and is not clear in human. Moreover, several studies suggest that this distribution changes during the development and heart diseases. However, the consequences of NCX and PMCA redistribution in human ventricular cardiomyocytes have not yet been elucidated. In this study, we aimed to address this point by using a mathematical model of the human ventricular myocyte incorporating t-tubules, dyadic spaces, and subsarcolemmal spaces. Effects of various combinations of t-tubular fractions of NCX and PMCA were explored, using values between 0.2 and 1 as reported in animal experiments under normal and pathological conditions. Small variations in the action potential duration (≤ 2%), but significant changes in the peak value of cytosolic Ca²⁺ transient (up to 17%) were observed at stimulation frequencies corresponding to the human heart rate at rest and during activity. The analysis of model results revealed that the changes in Ca²⁺ transient induced by redistribution of NCX and PMCA were mainly caused by alterations in Ca²⁺ concentrations in the subsarcolemmal spaces and cytosol during the diastolic phase of the stimulation cycle. The results suggest that redistribution of both transporters between the t-tubular and surface membranes contributes to changes in contractility in human ventricular cardiomyocytes during their development and heart disease and may promote arrhythmogenesis.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"193 ","pages":"Pages 113-124"},"PeriodicalIF":4.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}