Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase

Circulation, Journal Year: 2020, Volume and Issue: 142(25), P. 2443 - 2455

Published: Oct. 23, 2020

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. also increases the risk of atrial fibrillation (AF), which remains poorly understood. Methods: We performed electrophysiology studies on mice treated ibrutinib to assess inducibility AF. Chemoproteomic analysis cardiac lysates identified candidate targets, were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried determine whether drug inhibition an associated increased reporting Results: demonstrate that treatment for 4 weeks results inducible AF, left enlargement, myocardial fibrosis, inflammation. This effect reproduced lacking kinase, but not acalabrutinib, more specific inhibitor, demonstrating AF off-target side effect. profiling short list kinases narrowed by experimentation leaving CSK (C-terminal Src kinase) as strongest ibrutinib-induced Cardiac-specific Csk knockout led inflammation, phenocopying treatment. Disproportionality analyses VigiBase confirmed inhibitors blocking versus non-Csk inhibitors, odds ratio 8.0 (95% CI, 7.3–8.7; P <0.0001). Conclusions: These data identify mechanism through leads Registration: URL: https://ww.clinicaltrials.gov ; Unique identifier: NCT03530215.

Language: Английский

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Immune Cells and Immunotherapy for Cardiac Injury and Repair

Circulation Research, Journal Year: 2021, Volume and Issue: 128(11), P. 1766 - 1779

Published: May 27, 2021

Cardiac injury remains a major cause of morbidity and mortality worldwide. Despite significant advances, full understanding why the heart fails to fully recover function after acute injury, progressive failure frequently ensues, elusive. No therapeutics, short transplantation, have emerged reliably halt or reverse inexorable progression in majority patients once it has become clinically evident. To date, most pharmacological interventions focused on modifying hemodynamics (reducing afterload, controlling blood pressure volume) cardiac myocyte function. However, important contributions immune system normal response recently as exciting areas investigation. Therapeutic aimed at harnessing power cells hold promise for new treatment avenues disease. Here, we review its contribution fibrosis, potential therapies affect repair.

Language: Английский

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Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload

Cell Death and Disease, Journal Year: 2020, Volume and Issue: 11(7)

Published: July 24, 2020

Abstract Chronic heart failure (CHF) is the final outcome of many cardiovascular diseases, and a severe health issue faced by elderly population. Mixed lineage kinase 3 (MLK3), member MAP3K family, associated with aging, inflammation, oxidative stress, related such as CHF. MLK3 has also been reported to play an important role in protecting against cardiomyocyte injury; however, its function myocardial fibrosis unknown. To investigate fibrosis, we inhibited expression MLK3, examined cardiac remodeling TAC mice. In addition, assessed protein ventricular cells downstream protein. We found that mainly regulates NF-κB/NLRP3 signaling pathway-mediated inflammation pyroptosis causes early stages Similarly, JNK/p53 stress ferroptosis advanced promoting miR-351 can inhibit significantly improve mice subjected TAC. These results suggest induced cardiomyocytes are essential for adverse response pressure overload. Furthermore, miR-351, which protective effect on caused overload, may be key target regulation MLK3.

Language: Английский

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Inflammasomes as therapeutic targets in human diseases

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: July 2, 2021

Abstract Inflammasomes are protein complexes of the innate immune system that initiate inflammation in response to either exogenous pathogens or endogenous danger signals. Inflammasome multiprotein composed three parts: a sensor protein, an adaptor, and pro-caspase-1. Activation inflammasome leads activation caspase-1, which cleaves pro-inflammatory cytokines such as IL-1β IL-18, leading pyroptosis. Effectors not only provide protection against infectious pathogens, but also mediate control over sterile insults. Aberrant signaling has been implicated development cardiovascular metabolic diseases, cancer, neurodegenerative disorders. Here, we review role double-edged sword various outcomes can be good bad depending on disease, well genetic background. We highlight memory two-shot process. propose M- N-type model, discuss how pathway may targeted for novel therapy.

Language: Английский

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NLRP3 inflammasome, an immune‐inflammatory target in pathogenesis and treatment of cardiovascular diseases

Clinical and Translational Medicine, Journal Year: 2020, Volume and Issue: 10(1), P. 91 - 106

Published: March 1, 2020

Abstract Inflammation is an important process involved in several cardiovascular diseases (CVDs), and nod‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome a vital player innate immunity inflammation. In this review, we aim to provide comprehensive summary of the current knowledge on role involvement NLRP3 pathogenesis treatment CVDs. functions as molecular platform, triggers activation caspase‐1 cleavage pro‐IL‐1β, pro‐IL‐18, gasdermin D (GSDMD). Cleaved NT‐GSDMD forms pores cell membrane initiates pyroptosis, inducing death release many intracellular pro‐inflammatory molecules. triggered via inter‐related pathways downstream K + efflux, lysosomal disruption, mitochondrial dysfunction. addition, Golgi apparatus noncoding RNAs are gradually being recognized play roles activation. Many investigations have revealed association between CVDs, including atherosclerosis, ischemia/reperfusion (I/R) injury heart failure induced by pressure overload or cardiomyopathy. Some existing medications, orthodox natural medicines, used for CVD been newly discovered act inflammasome. pathway components such NLRP3, caspase‐1, IL‐1β may be considered novel therapeutic targets Thus, key molecule further research focused development inflammasome‐based targeted therapies CVDs clinical evaluation these essential.

Language: Английский

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Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 20(3), P. 145 - 167

Published: Sept. 15, 2022

Language: Английский

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The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases

Nature Reviews Cardiology, Journal Year: 2023, Volume and Issue: 21(4), P. 219 - 237

Published: Nov. 3, 2023

Language: Английский

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Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2021, Volume and Issue: 12(6), P. 1653 - 1668

Published: Sept. 2, 2021

Language: Английский

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NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload

Circulation, Journal Year: 2022, Volume and Issue: 147(4), P. 338 - 355

Published: Nov. 28, 2022

Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, regulatory mechanism of its role in stressed remain unclear. IL-1β (interleukin-1β) is a proinflammatory cytokine that cardiac hypertrophy failure. Here, we show neural signals activate NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for production to induce adaptive heart.C57BL/6 mice, knockout mouse strains P2RX7 (P2X purinoceptor 7), adrenergic neuron-specific mice SLC17A9, secretory vesicle protein responsible storage release ATP, were used analysis. Pressure overload was induced by transverse aortic constriction. Various animal models used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')-O-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1β antibodies, clonidine, pseudoephedrine, isoproterenol, bisoprolol, left stellate ganglionectomy, ablation afferent nerves capsaicin. Cardiac function morphology, gene expression, myocardial caspase-1 activity, extracellular ATP level assessed. In vitro experiments performed using primary cardiomyocytes fibroblasts from rat neonates human microvascular endothelial cell line. Cell surface area proliferation assessed.Genetic disruption resulted significant loss production, hypertrophy, contractile during pressure overload. A bone marrow transplantation experiment revealed an essential nonimmune cells phenotype. Pharmacological depletion or genetic P2X7 receptor suppressed activity overload, indicating important ATP/P2X7 axis hypertrophy. Extracellular changes NLRP3- IL-1β-dependent manner vitro. Manipulation sympathetic nervous system suggested efferent main source ATP. Depletion nerves, lipophilic β-blocker reduced level, inhibited activation, overload.Cardiac are regulated heart-brain interaction. Controlling might be hypertensive

Language: Английский

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Inflammasome Signaling in Atrial Fibrillation

Journal of the American College of Cardiology, Journal Year: 2022, Volume and Issue: 79(23), P. 2349 - 2366

Published: June 1, 2022

Language: Английский

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