Ephaptic coupling enables action potential conduction DOI Creative Commons

J. Waaben,

Johannes P. Hofgaard,

G.L. Pick

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 18, 2024

Abstract Background Cardiac action potentials are believed to propagate solely by electrotonic transmission via gap junctions. In the alternative theory of ephaptic transmission, changes in extracellular electrical fields and ion concentrations may enable a cardiomyocyte activate its neighbors. The involvement mechanisms remain highly disputed has been discounted due reported inability an isolated another. Methods Isolated rat cardiomyocytes were subjected whole cell patch clamp. Transmission was tested current clamp pushed together native pairs. Sodium channel activation inactivation voltage Results end-to-end one stimulated fire potential. 10 attempts, 2 pairs showed successful potentials, showing that is possible. pairs, subthreshold depolarization transferred between electrically coupled however, only after delay, which not be explained from theory. Once elicited pair, neighbor activated with delays under msec. delay did correlate junctional coupling, again suggesting presence mechanism. held at -90 mV while depolarizing pulses applied neighbor. Consistently, sodium channels depolarized led hyperpolarized cell, fits well but Ephaptic requires shielded local domain. To separate this, we measured steady state As expected, all inactivated -40 mV. However, when maintaining potential – 40 for extended period, 0 re-emerged de-inactivation. de-inactivation support domain exists where potassium currents can hyperpolarize Conclusions We show first time possible, it most likely operation, also finally our study suggests data obtained single cells fail reproduce key features electrophysiology interact neighboring cardiomyocytes.

Язык: Английский

AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans DOI
Chantal J.M. van Opbergen, Bitha Narayanan,

Chester Bittencourt Sacramento

и другие.

Circulation Genomic and Precision Medicine, Год журнала: 2024, Номер 17(1)

Опубликована: Янв. 30, 2024

Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available prevent or arrest the disease. We tested hypothesis that adeno-associated virus vector-mediated delivery of human

Язык: Английский

Процитировано

22
Meeting report – Alpine desmosome disease meeting 2024: advances and emerging topics in desmosomes and related diseases DOI Creative Commons
Jens Waschke, Masayuki Amagai, Christoph Becker

и другие.

Journal of Cell Science, Год журнала: 2025, Номер 138(2)

Опубликована: Янв. 15, 2025

Desmosomes are adhesive cell contacts abundant in tissues exposed to mechanical strain, such as the stratified and simple epithelia of epidermis mucous membranes, well myocardium. Besides their role cohesion, desmosomes also modulate pathways important for tissue differentiation, wound healing immune responses. Dysfunctional desmosomes, resulting from pathogenic variants genes encoding desmosomal components, autoantibodies targeting adhesion molecules or inflammation, cause life-threatening diseases arrhythmogenic cardiomyopathy pemphigus contribute pathogenesis inflammatory bowel diseases. The Alpine Desmosome Disease Meeting 2024 (ADDM 2024), held Grainau, Germany October 2024, connected international researchers basic sciences with clinical experts dermatology, cardiology, gastroenterology surgery. participants discussed recent advances, identified hot topics desmosome biology disease provided new concepts treatment approaches.

Язык: Английский

Процитировано

1
Susceptibility to innate immune activation in genetically-mediated myocarditis DOI Creative Commons
Daniel Selgrade, Dominic E. Fullenkamp, Ivana A. Chychula

и другие.

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(13)

Опубликована: Май 16, 2024

Background: Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, treatment for myocarditis often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated with biomarkers pathological features indistinguishable from other forms of myocarditis. DSP-associated can progress to dilated cardiomyopathy heightened arrhythmia risk. Methods: To model cardiomyocyte aspects assess role innate immunity, we generated engineered tissues (EHTs) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) patients gene-edited healthy control hiPSC lines. Homozygous heterozygous DSP disrupted EHTs were contain 90% hiPSC-CMs 10% cardiac fibroblasts. We measured immune activation function at baseline response Toll-like receptor (TLR) stimulation EHTs. Results: At baseline, DSP-/- displayed transcriptomic signature which was mirrored EHT cytokine release. Importantly, hypersensitive TLR demonstrating greater contractile impairment compared isogenic controls. Compared homozygous EHTs, patient-derived had less functionally but also sensitivity stimulation. When subjected strain, developed functional deficit indicating reduced reserve control. Colchicine or NFΚB inhibitors improved force production strain-induced deficits Genomic correction p.R1951X using adenine base editing inflammatory biomarker release Conclusions: Genetic reduction renders susceptible strain-dependent deficits. replicate electrical phenotypes seen implicating as key part myogenic susceptibility inflammation. This target clinical intervention.

Язык: Английский

Процитировано

6
Ultrastructure and cardiac impulse propagation: scaling up from microscopic to macroscopic conduction DOI Creative Commons
Zhilin Qu, Peter Hanna, Olujimi A. Ajijola

и другие.

The Journal of Physiology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 29, 2024

Abstract The standard conception of cardiac conduction is based on the cable theory nerve conduction, which treats tissue as a continuous syncytium described by Hodgkin–Huxley equations. However, composed discretized cells with microscopic and macroscopic heterogeneities discontinuities, such subcellular localizations sodium channels connexins. In addition to this, there are in distribution sympathetic parasympathetic nerves, powerfully regulate impulse propagation. models, ultrastructural details, i.e. ignored ‘coarse graining’ or ‘smoothing’. these components may play crucial roles arrhythmogenesis, particularly disease states. We discuss current progress modelling effects electrical issues challenges faced community, how scale up properties at (microscopic) whole‐heart (macroscopic) future experimental studies, link ultrastructure different scales arrhythmogenesis heart. image

Язык: Английский

Процитировано

4
High-Sensitivity Top-Down Proteomics Reveals Enhanced Maturation of Micropatterned Induced Pluripotent Stem Cell-Derived Cardiomyocytes DOI
MALLORY C. WILSON, Mitchell Josvai,

Janay K. Walters

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Май 15, 2025

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used for disease modeling, drug discovery, and precision medicine, yet their utility is often limited by immature phenotype. One promising maturation strategy involves using micropatterned substrates that mimic native cardiomyocytes' organizational growth stiffness. However, the molecular maturity of this model has not been assessed, there currently no method to extract proteins from hiPSC-CMs top-down proteomic analysis. Herein, we present a high-sensitivity, surfactant-free protein extraction protocol analysis hiPSC-CMs. Through method, assessed compared traditional unstructured monoculture co-culture monolayers at proteoform level. We found display signatures cardiomyocyte maturations including increased expression ventricular myosin light chain isoforms, reduced fetal troponin T isoform, decreased phosphorylation alpha-tropomyosin. This surfactant-free, high-sensitivity approach enables robust proteomics limited, heterogeneous cell populations, identifies micropattern hiPSC-CM as more adult-like CM model, broadening structured culture systems cardiac modeling translational research.

Язык: Английский

Процитировано

0
Exercise-induced dysregulation of the adrenergic response in a mouse model of PKP2-arrhythmogenic cardiomyopathy DOI
Chantal J.M. van Opbergen, Lilian K. Gutiérrez, Giorgia Bertoli

и другие.

Heart Rhythm, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0
Gap junctional and ephaptic coupling in cardiac electrical propagation: homocellular and heterocellular perspectives DOI Creative Commons
Xiaobo Wu, Laura Beth Payne, Robert G. Gourdie

и другие.

The Journal of Physiology, Год журнала: 2025, Номер unknown

Опубликована: Май 31, 2025

Abstract Electrical communication in the heart is crucial for maintaining normal cardiac function. Traditionally, gap junctional coupling between cardiomyocytes has been accepted as primary mechanism governing electrical propagation heart. However, numerous studies have demonstrated that junctions are also present different cell types heterocellular structures and disruption of such can be associated with dysfunction. In addition to coupling, ephaptic proposed another cardiomyocytes. Reducing shown negative impacts on conduction. While existence under investigation, a recent study suggests at contacts fibroblasts may provide proarrhythmic substrate disease. this review, we examine current literature heart, including homocellular contexts. Further, offer perspective gaps knowledge opportunities further advancing our understanding mechanisms action potential image

Язык: Английский

Процитировано

0
Arrhythmogenic cardiomyopathy as a myogenic disease: highlights from cardiomyocytes derived from human induced pluripotent stem cells DOI Creative Commons
Jean‐Baptiste Reisqs, Adrien Moreau, Yvonne Sleiman

и другие.

Frontiers in Physiology, Год журнала: 2023, Номер 14

Опубликована: Май 11, 2023

Arrhythmogenic cardiomyopathy (ACM) is an inherited characterized by the replacement of myocardium fibro-fatty infiltration and cardiomyocyte loss. ACM predisposes to a high risk for ventricular arrhythmias. has initially been defined as desmosomal disease because most known variants causing concern genes encoding proteins. Studying this pathology complex, in particular human samples are rare and, when available, reflect advanced stages disease. Usual cellular animal models cannot reproduce all hallmarks pathology. In last decade, human-induced pluripotent stem cells (hiPSC) have proposed innovative model. The differentiation hiPSCs into cardiomyocytes (hiPSC-CM) now well-controlled widely used many laboratories. This hiPSC-CM model recapitulates critical features enables cardiomyocyte-centered comprehensive approach screening anti-arrhythmic drugs (AAD) prescribed sometimes empirically patient. regard, provides unique opportunities explore develop new therapeutic approaches. use hiPSC-CMs will undoubtedly help development precision medicine better cure patients suffering from ACM. review aims summarize recent advances allowing context.

Язык: Английский

Процитировано

7
AAV-mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans DOI Open Access

Chantal J. van Opbergen,

Bitha Narayanan,

Chester Bittencourt Sacramento

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 12, 2023

ABSTRACT Background Pathogenic variants in plakophilin-2 (PKP2) cause arrhythmogenic right ventricular cardiomyopathy (ARVC), a disease characterized by life-threatening arrhythmias and progressive leading to heart failure. No effective medical therapy is available prevent and/or arrest the disease. We tested hypothesis that AAV-mediated delivery of human PKP2 gene an adult mammalian deficient can progression significantly prolong survival. Methods Experiments were carried out using cardiac-specific, tamoxifen (TAM)-activated knockout murine model (PKP2-cKO). The potential therapeutic, AAVrh.74-PKP2a (RP-A601), recombinant AAVrh.74 viral vector encoding variant A (PKP2a). was delivered mice single tail vein injection either before or after TAM-activated PKP2-cKO. expression confirmed molecular histopathologic analyses. Cardiac function monitored survival analyses, echocardiography electrocardiography. Results Consistent with prior findings, loss caused 100% mortality within 50 days TAM injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a resulted for more than 5 months (at study termination). Echocardiographic analysis revealed prevented ventricle dilation, arrested left functional decline, mitigated arrhythmia burden. Molecular histological showed AAVrh.74-PKP2a– mediated transgene mRNA protein appropriate localization at cardiomyocyte intercalated disc. Importantly, therapeutic benefit shown receiving onset. Conclusion These preclinical data demonstrate (RP-A601) as PKP2-related ARVC both early advanced stages

Язык: Английский

Процитировано

7
Genetic inactivation of β-catenin is salubrious, whereas its activation is deleterious in desmoplakin cardiomyopathy DOI Open Access
Melis Olcum,

Siyang Fan,

Leila Rouhi

и другие.

Cardiovascular Research, Год журнала: 2023, Номер 119(17), С. 2712 - 2728

Опубликована: Авг. 23, 2023

Mutations in the DSP gene encoding desmoplakin, a constituent of desmosomes at intercalated discs (IDs), cause phenotype that spans arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy. It is typically characterized by biventricular enlargement dysfunction, myocardial fibrosis, cell death, arrhythmias. The canonical wingless-related integration (cWNT)/β-catenin pathway implicated pathogenesis ACM. β-catenin an indispensable co-transcriptional regulator cWNT member IDs. We genetically inactivated or activated to determine its role desmoplakin

Язык: Английский

Процитировано

7