Progress on role of ion channels of cardiac fibroblasts in fibrosis

Frontiers in Physiology, Journal Year: 2023, Volume and Issue: 14

Published: March 9, 2023

Cardiac fibrosis is defined as excessive deposition of extracellular matrix (ECM) in pathological conditions. fibroblasts (CFs) activated by injury or inflammation differentiate into myofibroblasts (MFs) with secretory and contractile functions. In the fibrotic heart, MFs produce ECM which composed mainly collagen initially involved maintaining tissue integrity. However, persistent disrupts coordination excitatory coupling, leading to systolic diastolic dysfunction, ultimately heart failure. Numerous studies have demonstrated that both voltage- non-voltage-gated ion channels alter intracellular levels cellular activity, contributing myofibroblast proliferation, contraction, function. an effective treatment strategy for myocardial has not been established. Therefore, this review describes progress made research related transient receptor potential (TRP) channels, Piezo1, Ca 2+ release-activated (CRAC) voltage-gated (VGCCs), sodium potassium aim providing new ideas treating fibrosis.

Language: Английский

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Protein prenylation in mechanotransduction: implications for disease and therapy

Trends in Pharmacological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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IL-11 promotes Ang II-induced autophagy inhibition and mitochondrial dysfunction in atrial fibroblasts

Open Life Sciences, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 1, 2025

Abstract This study aimed to investigate potential targets for the pathogenesis of atrial fibrillation facilitate development effective treatments. Atrial fibroblasts were isolated and stimulated with 1 μM angiotensin-II (Ang-II) 24 h. To increase interleukin 11 (IL-11) expression, overexpression plasmids transfected into fibroblasts. The role underlying mechanism IL-11 in examined by immunofluorescence, measurements reactive oxygen species (ROS) mitochondrial membrane (MMP), western blotting assays. Results demonstrated that was upregulated Ang-II-elicited Ang-II treatment increases alpha-smooth muscle actin (α-SMA), ROS MMP levels, p62 expression but decreases microtubule-associated protein light chain 3 II/I (LC3 II/I) Beclin-1 expressions These effects further amplified overexpression. Mechanistically, mammalian target rapamycin (mTOR) pathway enhanced Ang-II-induced fibroblasts, which elevated upregulation. facilitates Ang II-induced differentiation myofibroblasts promoting oxidative stress, dysfunction, autophagy inhibition through mTOR pathway.

Language: Английский

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In Vitro Mechanical Stimulation to Reproduce the Pathological Hallmarks of Human Cardiac Fibrosis on a Beating Chip and Predict The Efficacy of Drugs and Advanced Therapies

Advanced Healthcare Materials, Journal Year: 2023, Volume and Issue: 13(4)

Published: Nov. 9, 2023

Abstract Cardiac fibrosis is one of the main causes heart failure, significantly contributing to mortality. The discovery and development effective therapies able heal fibrotic pathological symptoms thus remain paramount importance. Micro‐physiological systems (MPS) are recently introduced as promising platforms accelerate this finding. Here a 3D in vitro model human cardiac fibrosis, named uScar, developed by imposing cyclic mechanical stimulation atrial fibroblasts (AHCFs) cultured beating heart‐on‐chip exploited screen drugs advanced therapeutics. sole provision 10% uniaxial strain at 1 Hz microtissues sufficient trigger traits, inducing consistent fibroblast‐to‐myofibroblast transition an enhanced expression production extracellular matrix (ECM) proteins. Standard care anti‐fibrotic (i.e., Pirfenidone Tranilast) confirmed be efficient preventing onset traits uScar. Conversely, applied limit ability miRNA therapy directly reprogram into cardiomyocytes (CMs), despite its proved efficacy 2D models. Such results demonstrate importance incorporating vivo‐like stimulations generate more representative models predict patients.

Language: Английский

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Multiphysics simulations reveal haemodynamic impacts of patient‐derived fibrosis‐related changes in left atrial tissue mechanics

The Journal of Physiology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 8, 2024

Stroke is a leading cause of death and disability worldwide. Atrial myopathy, including fibrosis, associated with an increased risk ischaemic stroke, but the mechanisms underlying this association are poorly understood. Fibrosis modifies myocardial structure, impairing electrical propagation tissue biomechanics, creating stagnant flow regions where clots could form. can be mapped non-invasively using late gadolinium enhancement magnetic resonance imaging (LGE-MRI). However, fibrosis maps not currently incorporated into stroke calculations or computational electro-mechano-fluidic models. We present multiphysics simulations left atrial (LA) motion haemodynamics patient-specific anatomies fibrotic from LGE-MRI. modify stiffness active tension generation in investigate how these changes affect LA for different burdens. find that and, to lesser extent, non-fibrotic experience reduced strain, resulting decreased emptying fraction consistent clinical observations. Both stiffening hypocontractility independently reduce function, but, together, two alterations more pronounced effects than either one alone. significantly alters patterns throughout chamber, particularly, filling jets appendage (LAA). The largely captured by concomitant except inside LAA, multifactorial behaviour observed. This work illustrates high-fidelity, models used study thrombogenesis anatomies, shedding light onto links between stroke. KEY POINTS: Left arrhythmogenesis stroke; its extent pattern quantified on basis imaging. Current prediction tools have limited personalization, their accuracy improved incorporating information such as haemodynamic patterns. first flow, medical Mechanical impair global motion, decreasing (LAA) fractions, especially subjects higher Fibrotic-mediated impairment LAA near endocardium whole cavity, ultimately blood LAA.

Language: Английский

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Personalized biomechanical insights in atrial fibrillation: opportunities & challenges

Expert Review of Cardiovascular Therapy, Journal Year: 2023, Volume and Issue: 21(11), P. 817 - 837

Published: Oct. 25, 2023

Atrial fibrillation (AF) is an increasingly prevalent and significant worldwide health problem. Manifested as irregular atrial electrophysiological activation, it associated with many serious complications. AF affects the biomechanical function of heart contraction follows electrical subsequently leading to reduced blood flow. The underlying mechanisms behind are not fully understood, but known that highly correlated presence fibrosis, a manifold increase in risk stroke.

Language: Английский

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Early Impairment of Paracrine and Phenotypic Features in Resident Cardiac Mesenchymal Stromal Cells after Thoracic Radiotherapy

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2873 - 2873

Published: March 1, 2024

Radiotherapy-induced cardiac toxicity and consequent diseases still represent potential severe late complications for many cancer survivors who undergo therapeutic thoracic irradiation. We aimed to assess the phenotypic paracrine features of resident mesenchymal stromal cells (CMSCs) at early follow-up after end irradiation heart as an sign and/or mechanism anticipating organ dysfunction. Resident CMSCs were isolated from a rat model fractionated with accurate clinically relevant dosimetry that developed delayed dose-dependent dysfunction 1 year. Cells 6 12 weeks radiotherapy fully characterized transcriptional, paracrine, functional levels. displayed several altered in dose- time-dependent trend, most impaired characteristics observed those exposed situ highest radiation dose time. In particular, included cell migration 3D growth significant association transcriptomic data GO terms related cytokine factor signaling. Indeed, profile derived group 12-week gave significantly reduced angiogenic support endothelial polarized macrophages toward pro-inflammatory profile. Data collected simulating suggest transcriptional alterations stroma may biological substrate phenotype vivo.

Language: Английский

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Patient-specific multi-physics simulations of fibrotic changes in left atrial tissue mechanics impact on hemodynamics

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 30, 2024

Stroke is a leading cause of death and disability worldwide. Atrial myopathy, including fibrosis, associated with an increased risk ischemic stroke, but the mechanisms underlying this association are poorly understood. Fibrosis modifies myocardial structure, impairing electrical propagation tissue biomechanics, creating stagnant flow regions where clots could form. can be mapped non-invasively using late gadolinium enhancement magnetic resonance imaging (LGE-MRI). However, fibrosis maps not currently incorporated into stroke calculations or computational electro-mechano-fluidic models. We present multi-physics simulations left atrial (LA) motion hemodynamics patient-specific anatomies fibrotic from LGE-MRI. modify stiffness active tension generation in investigate how these changes affect LA for different burdens. find that and, to lesser extent, non-fibrotic experience reduced strain, resulting decreased emptying fraction consistent clinical observations. Both stiffening hypocontractility independently reduce function, together, two alterations more pronounced effects than either one alone. significantly alters patterns throughout chamber, particularly, filling jets appendage (LAA). The largely captured by concomitant except inside LAA, multi-factorial behavior observed. This work illustrates high-fidelity, models used study thrombogenesis anatomies, shedding light onto links between stroke.

Language: Английский

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Construction of cardiac fibrosis for biomedical research

Smart Medicine, Journal Year: 2023, Volume and Issue: 2(3)

Published: Aug. 1, 2023

Cardiac remodeling is critical for effective tissue recuperation, nevertheless, excessive formation and deposition of extracellular matrix components can result in the onset cardiac fibrosis. Despite emergence novel therapies, there are still no lifelong therapeutic solutions this issue. Understanding detrimental may aid development innovative treatment strategies to prevent or reverse fibrotic alterations heart. Further combining latest understanding disease pathogenesis with engineering has provided conversion basic laboratory studies into therapy fibrosis patients as an increasingly viable prospect. This review presents current main mechanisms potential Approaches using biomedical materials-based constructions reviewed consider key issues simulating vitro fibrosis, outlining a future perspective preclinical applications.

Language: Английский

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LncRNA CFRL aggravates cardiac fibrosis by modulating both miR-3113-5p/CTGF and miR-3473d/FN1 axis

iScience, Journal Year: 2023, Volume and Issue: 26(10), P. 108039 - 108039

Published: Sept. 26, 2023

Cardiac fibrosis is a major type of adverse remodeling, predisposing the disease progression to ultimate heart failure. However, complexity pathogenesis has hampered development therapies. One key mechanisms cardiac diseases recently been identified as long non-coding RNA (lncRNA) dysregulation. Through in vitro and vivo studies, we an lncRNA NONMMUT067673.2, which named related (CFRL). CFRL was significantly increased both mouse model cell fibrosis. In vitro, proved promote proliferation migration fibroblasts by competitively binding miR-3113-5p miR-3473d indirectly up-regulating CTGF FN1. vivo, silencing mitigated improved left ventricular function. short, may exert essential role interfering with might be considered multitarget strategy for

Language: Английский

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