Regulated cell death pathways in doxorubicin-induced cardiotoxicity

Cell Death and Disease, Год журнала: 2021, Номер 12(4)

Опубликована: Апрель 1, 2021

Abstract Doxorubicin is a chemotherapeutic drug used for the treatment of various malignancies; however, patients can experience cardiotoxic effects and this has limited use potent drug. The mechanisms by which doxorubicin kills cardiomyocytes been elusive despite extensive research exact remain unknown. This review focuses on recent advances in our understanding induced regulated cardiomyocyte death pathways including autophagy, ferroptosis, necroptosis, pyroptosis apoptosis. Understanding leads to may help identify novel therapeutic agents lead more targeted approaches cardiotoxicity testing.

Язык: Английский

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Molecular mechanisms of arrhythmogenic cardiomyopathy

Nature Reviews Cardiology, Год журнала: 2019, Номер 16(9), С. 519 - 537

Опубликована: Апрель 25, 2019

Язык: Английский

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Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Янв. 8, 2024

Abstract Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of intricate mechanisms underlying I/R hinders development effective therapeutic interventions. Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system pathways involved in injury. This review article elucidates signaling, as well complex interplay between and including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca 2+ -Activin A, Hippo-Yes-associated toll-like receptor 4/toll-interleukine-1 domain-containing adapter-inducing interferon-β, hepatocyte factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, apoptosis, inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, blood-brain barrier damage Our comprehensive analysis reveals that activation canonical promotes organ recovery, while non-canonical exacerbates Moreover, explore novel approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, clinical trials. objective this is provide deeper insights roles its I/R-mediated processes dysfunction, facilitate innovative agents for

Язык: Английский

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Non-canonical WNT signalling in cardiovascular disease: mechanisms and therapeutic implications

Nature Reviews Cardiology, Год журнала: 2022, Номер 19(12), С. 783 - 797

Опубликована: Июнь 13, 2022

Язык: Английский

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The intercalated disc: a unique organelle for electromechanical synchrony in cardiomyocytes

Physiological Reviews, Год журнала: 2023, Номер 103(3), С. 2271 - 2319

Опубликована: Фев. 2, 2023

The intercalated disc (ID) is a highly specialized structure that connects cardiomyocytes via mechanical and electrical junctions. Although described in some detail by light microscopy the 19th century, it was 1966 electron images showed ID represented apposing cell borders provided detailed insight into complex nanostructure. Since then, much has been learned about its molecular composition, become evident large number of proteins, not all them involved direct cell-to-cell coupling or gap junctions, reside at ID. Furthermore, an increasing functional interactions between components are emerging, leading to concept sum isolated silos but interacting complex, “organelle” where work concert bring synchrony. aim present review give short historical account ID’s discovery updated overview composition organization, followed discussion physiological implications architecture local intermolecular interactions. latter will focus on both importance normal conduction cardiac action potentials as well impact pathophysiology arrhythmias.

Язык: Английский

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Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy

Current Heart Failure Reports, Год журнала: 2021, Номер 18(6), С. 378 - 390

Опубликована: Сен. 3, 2021

Abstract Purpose of Review Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations genes encoding for cellular junctions can be found about half the patients. However, onset severity, risk arrhythmias, outcome are highly variable drug-targeted treatment currently unavailable. Recent Findings This review focuses on advances clinical stratification, etiology, pathophysiological concepts. The desmosome central part disease, but other intercalated disc associated structural proteins not only broaden spectrum also provide novel molecular insights into pathogenesis ACM. Signaling pathways role inflammation will discussed targets therapeutic approaches outlined. Summary Genetic discoveries experimental-driven preclinical research contributed significantly to understanding ACM towards mutation- pathway-specific personalized medicine.

Язык: Английский

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Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis

Science Translational Medicine, Год журнала: 2022, Номер 14(669)

Опубликована: Ноя. 2, 2022

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to combinatorial anti–programmed cell death 1 and anti–cytotoxic T lymphocyte antigen–4 antibodies also presented cardiovascular toxicities observed clinically ICI therapy, including myocarditis arrhythmia. Female were preferentially affected compared male mice, consistent a previously described genetic model of emerging clinical data. Mechanistically, myocardial tissue from ICI-treated the mouse model, human heart patients all down-regulation MANF (mesencephalic astrocyte–derived neurotrophic factor) HSPA5 (heat shock 70-kDa protein 5) heart; this was particularly notable female mice. amplified by heart-specific deletion Manf attenuated administration recombinant protein, suggesting causal role. Ironically, both transcriptionally induced liganded estrogen receptor β inhibited androgen receptor. However, reduced serum estradiol concentration greater extent Treatment an β–specific agonist depletion therapy ICI-associated cardiac effects. Together, our data suggest inhibits estradiol-dependent expression MANF/HSPA5 heart, curtailing cardiomyocyte immune injury. This endocrine-cardiac-immune pathway offers new insights into mechanisms sex differences disease may offer strategies

Язык: Английский

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Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy

Science Translational Medicine, Год журнала: 2023, Номер 15(688)

Опубликована: Март 22, 2023

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly plakophilin-2 ( PKP2 ). Although the genetic basis of well characterized, underlying disease-driving mechanisms remain unresolved. Explanted hearts from had less compared healthy hearts, which correlated reduced expression and adherens junction (AJ) proteins. These proteins were also disorganized areas fibrotic remodeling. In vitro data human-induced pluripotent stem cell–derived cardiomyocytes microtissues carrying heterozygous c.2013delC pathogenic mutation displayed impaired contractility. Knockin mice equivalent Pkp2 c.1755delA recapitulated changes AJ dysfunction fibrosis age. Global proteomics analysis 4-month-old indicated involvement ubiquitin-proteasome system (UPS) pathogenesis. Inhibition UPS mutant increased area composita improved calcium dynamics isolated cardiomyocytes. Additional analyses identified lysine ubiquitination sites on proteins, more ubiquitinated mice. summary, we show that a can lead to decreased protein through UPS-dependent mechanism, preceded findings suggest targeting degradation improving stability may be potential therapeutic strategy for treatment ACM.

Язык: Английский

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Arrhythmogenic cardiomyopathy: pathogenesis, pro-arrhythmic remodelling, and novel approaches for risk stratification and therapy

Cardiovascular Research, Год журнала: 2020, Номер 116(9), С. 1571 - 1584

Опубликована: Март 30, 2020

Abstract Arrhythmogenic cardiomyopathy (ACM) is a life-threatening cardiac disease caused by mutations in genes predominantly encoding for desmosomal proteins that lead to alterations the molecular composition of intercalated disc. ACM characterized progressive replacement cardiomyocytes fibrofatty tissue, ventricular dilatation, dysfunction, and heart failure but mostly dominated occurrence arrhythmias sudden death (SCD). As SCD appears apparently healthy young individuals, there demand better risk stratification suspected mutation carriers. Moreover, severity, progression, outcome are highly variable patients with ACM. In this review, we discuss aetiology focus on pro-arrhythmic mechanisms early concealed phase disease. We summarize potential new biomarkers which might be useful prediction course. Finally, explore novel therapeutic strategies prevent stages

Язык: Английский

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A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signalling and miRNA dysregulation

Cardiovascular Research, Год журнала: 2018, Номер 115(4), С. 739 - 751

Опубликована: Окт. 9, 2018

Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death shows wide inter- intra-familial variability. Among causative genes identified so far, those encoding for desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2) are commonly mutated. So little known about molecular mechanism(s) behind such a varied spectrum phenotypes, although it has been shown that mutations not only lead to structural abnormalities but also affect miRNA profiling cardiac tissue. Here, we aimed at studying pathogenic effects nonsense mutation gene, both level terms expression pattern. We generated transgenic mice cardiomyocyte-specific overexpression FLAG-tagged human harbouring Q558* found an patient. The hearts these showed signs fibrosis, decrease size number, reduction Wnt/β-catenin signalling. Genome-wide RNA-Seq performed Tg-hQ non-transgenic revealed 24 miRNAs were dysregulated animals. Further bioinformatic analyses selected suggested miR-217-5p, miR-499-5p, miR-708-5p might be involved pathogenesis disease. Down-regulation canonical signalling considered key event pathogenesis. signature hearts, miR-217-5p being up-regulated miR-499-5p down-regulated miRNAs. All them predicted regulation pathway reveal potential pathophysiology mechanisms AC, as well useful therapeutic targets

Язык: Английский

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