The interplay of inflammation, exosomes and Ca2+ dynamics in diabetic cardiomyopathy

Cardiovascular Diabetology, Год журнала: 2023, Номер 22(1)

Опубликована: Фев. 20, 2023

Abstract Diabetes mellitus is one of the prime risk factors for cardiovascular complications and linked with high morbidity mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, chronic heart failure. Inflammation, changes in calcium (Ca 2+ ) handling cardiomyocyte loss are implicated development progression DCM. Although existence DCM was established nearly four decades ago, exact mechanisms underlying this disease pathophysiology constantly evolving. Furthermore, complex exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, lipids. Inflammatory response Ca signaling interrelated been known adversely affect many these molecules either qualitatively and/or quantitatively. In literature review, we have demonstrated that regulators tightly controlled at different molecular cellular levels during various biological processes heart. mediators, miRNA exosomes interact regulators, however how mediators pathogenesis remains elusive. Thus, further investigations needed understand restore homeostasis function, serve potential therapeutic targets treatment

Язык: Английский

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Reversible and Irreversible Effects of Electroporation on Contractility and Calcium Homeostasis in Isolated Cardiac Ventricular Myocytes

Circulation Arrhythmia and Electrophysiology, Год журнала: 2022, Номер 15(11)

Опубликована: Окт. 28, 2022

Irreversible electroporation is an energy form utilizing high-voltage pulsed electric field, leading to cellular homeostasis disruption and cell death. Recently, irreversible has shown promising results for the treatment of cardiac arrhythmias. However, reversible effects field on myocytes remain poorly understood. Here, we evaluated influence a monophasic single pulse (EP) contractility, Ca2+ recovery myocytes.Isolated rat left ventricular were electroporated using EP different durations voltages. Sarcomere length intracellular simultaneously monitored up 20 minutes after application in Fura-2 loaded myocytes. Lethal voltage thresholds determined 100 µs 10 ms pulses by discriminating orientation with respect field.Electroporation led immediate increase which was dependent upon delivered cell. Intermediate-voltage (140 V, µs) increased sarcomere shortening, transient amplitude, diastolic level measured 1 minute post-EP. Although shortening returned pre-EP within 5 minutes, amplitude decreased further below remained elevated Spontaneous contractions observed sublethal but their frequency progressively minutes. threshold lower oriented perpendicular than parallel while opposite effect found pulses.Sublethal affected contractility disrupted as function voltage. Moreover, EP-induced lethality preceded large duration, field. These findings provide new insights into

Язык: Английский

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From Millimeters to Micrometers; Re-introducing Myocytes in Models of Cardiac Electrophysiology

Frontiers in Physiology, Год журнала: 2021, Номер 12

Опубликована: Окт. 27, 2021

Computational modeling has contributed significantly to present understanding of cardiac electrophysiology including conduction, excitation-contraction coupling, and the effects side-effects drugs. However, accuracy in silico analysis electrochemical wave dynamics tissue is limited by homogenization procedure (spatial averaging) intrinsic standard continuum models conduction. Averaged cannot resolve intricate vicinity individual cardiomyocytes simply because myocytes are not these models. Here we demonstrate how recently developed mathematical based on representing every myocyte can increase accuracy, thus utility electrophysiological function dysfunction collections coupled cardiomyocytes. The gold numerical simulation for bidomain model. In model, extracellular (E) space, cell membrane (M) intracellular (I) space all assumed be everywhere tissue. Consequently, it impossible study biophysical processes taking place close myocytes. model represents averaging over several hundred this inherently limits our alternative approach both E, M, I represented which therefore referred as EMI allows detailed going functionally important spaces very myocytes, although at cost increased CPU-requirements.

Язык: Английский

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Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives

Frontiers in Physiology, Год журнала: 2022, Номер 13

Опубликована: Март 9, 2022

Regulation of intracellular calcium is a critical component cardiac electrophysiology and excitation-contraction coupling. The spark, the fundamental element transient, initiated in specialized nanodomains which co-locate ryanodine receptors L-type channels. However, homeostasis ultimately regulated at cellular scale, by interaction spatially separated but diffusively coupled with other sub-cellular surface-membrane transport channels strong non-linear interactions; arrhythmia mechanisms are tissue-scale phenomena, heterogeneous population myocytes. Recent advances imaging modalities image-analysis enabling super-resolution reconstruction structures responsible for regulating homeostasis, including internal structure themselves. Extrapolating functional data from nanodomain to whole-heart non-trivial, yet essential translational insight into disease mechanisms. Computational modeling has important roles play relating structural scale translating across scales. This review covers recent methodological that enable image-based single whole cardiomyocyte, as well development multi-scale simulation approaches integrate nanometer whole-heart. Firstly, methods overcome computational challenges simulating spatial dynamics discussed, this scale. Then, whole-cell models, capable capturing range different (such T-system mitochondria) heterogeneity/variability discussed two levels discretization. Novel models scales simulate stochastic then elucidation remodeling underlies contractile dysfunction. Perspectives on model differences future directions provided throughout.

Язык: Английский

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Regulation of cardiomyocyte t‐tubule structure by preload and afterload: Roles in cardiac compensation and decompensation

The Journal of Physiology, Год журнала: 2024, Номер 602(18), С. 4487 - 4510

Опубликована: Апрель 30, 2024

Mechanical load is a potent regulator of cardiac structure and function. Although high workload during heart failure associated with disruption cardiomyocyte t-tubules Ca

Язык: Английский

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Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels

Frontiers in Physiology, Год журнала: 2022, Номер 12

Опубликована: Янв. 5, 2022

The architectural specializations and targeted delivery pathways of cardiomyocytes ensure that L-type Ca2+ channels (CaV1.2) are concentrated on the t-tubule sarcolemma within nanometers their intracellular partners type 2 ryanodine receptors (RyR2) which cluster junctional sarcoplasmic reticulum (jSR). organization distribution these two groups cardiac calcium channel clusters critically underlies uniform contraction myocardium. signaling between sets adjacent produces sparks in health, cannot escalate into waves because there is sufficient separation so release from one RyR2 or supercluster, activate sustain neighboring clusters. Instead, thousands units (CRUs) generate near simultaneous across every cardiomyocyte during action potential when induced stimulated by depolarization influx through voltage dependent CaV1.2 These summate to a global transient activates myofilaments thus electrical signal transduced functional output, myocardial contraction. To more, less contractile force match hemodynamic metabolic demands body, heart responds β-adrenergic altering activity tune excitation-contraction coupling accordingly. Recent accumulating evidence suggests this tuning process also involves altered expression, dynamic reorganization respective membranes control amplitude entry, SR function. In failure aging, key proteins occurs alongside remodeling thought contribute impaired present review we discuss latest developments, implications, future questions be addressed.

Язык: Английский

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Caveolin and oxidative stress in cardiac pathology

Frontiers in Physiology, Год журнала: 2025, Номер 16

Опубликована: Фев. 18, 2025

Caveolins interact with signaling molecules within caveolae and subcellular membranes. Dysregulation of caveolin function protein abundance contributes to cardiac pathophysiological processes, driving the development progression heart disease. Reactive oxygen species (ROS) play a critical role in maintaining cellular homeostasis are key contributors mechanisms cardiovascular disorders. have been shown modulate oxidative stress regulate redox homeostasis. However, specific roles caveolins, particularly caveolin-1 caveolin-3, regulating ROS production during pathology remain unclear. This mini-review article highlights correlation between caveolins health modulating diseases, specifically myocardial ischemia, failure, diabetes-induced metabolic cardiomyopathy, septic cardiomyopathy. A deeper understanding caveolin-mediated may pave way for innovative therapeutic approaches treat diseases.

Язык: Английский

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Cardiomyocyte T-System Remodeling in a Rat Model of Metabolic Syndrome

Journal of Evolutionary Biochemistry and Physiology, Год журнала: 2025, Номер 61(1), С. 96 - 104

Опубликована: Янв. 1, 2025

Язык: Английский

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Inhibiting NCX delays the early onset of Ca2+ alternans in myocytes from spontaneously hypertensive rats (SHR)

Journal of Molecular and Cellular Cardiology, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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AAV9-cBIN1 gene therapy rescues chronic heart failure due to ischemic cardiomyopathy in a canine model

Communications Medicine, Год журнала: 2025, Номер 5(1)

Опубликована: Март 27, 2025

Ischemic cardiomyopathy and resultant heart failure (HF) is a significant cause of morbidity mortality worldwide. Downregulation cardiac bridging integrator 1 (cBIN1), membrane scaffolding protein responsible for organizing t-tubules the calcium handing apparatus, occurs in progressive HF. Therefore, gene therapy upregulating cBIN1 production may rescue failing muscle clinical Adult mongrel dogs underwent ligation left anterior descending artery developed dilated chronic When ventricular ejection fraction (LVEF) dropped below 40%, animals received one-time series endocardial injections either low dose composed adeno-associated virus serotype 9 packaged (AAV9-cBIN1, n = 6) or AAV9-GFP (green fluorescent protein, 4). Animals were followed up to 7 weeks after delivery with laboratory, echocardiography, mapping assessment. Post injection negative control, develop symptomatic HF requiring early termination all but one animal prior end study. In contrast, AAV9-cBIN1-treated group reveals improvement LV function, noticeable LVEF (29 ± 3% vs. 42 2%, p 0.0095) global longitudinal strain (−7.1 0.9% −12.5 1.6%, 0.0095). Compared control animals, displays improved T-tubule morphology, chamber size, plasma biomarkers, voltage, survives study period. Chronic from ischemic can be successfully treated AAV9-cBIN1 therapy. This indicates that myocardial specific dramatically reverse progression. Blocked arteries are known damage by impairing ability pump blood, resulting eventual failure. Medical interventions recover needed prevent hospitalization death. Here, we replace an important tested it canine model induced blocked arteries. These findings show function survival rate following therapy, indicating potential this reduce syndrome Khan et al. perform acquired cardiomyopathy. They mitigates disease progression model.

Язык: Английский

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