scholarly journals Advances in Cardiac Development and Regeneration Using Zebrafish as a Model System for High-Throughput Research

2021 ◽  
Vol 9 (4) ◽  
pp. 40
Author(s):  
Nicholas Francoeur ◽  
Rwik Sen
Keyword(s):  
Heart Disease ◽  
Heart Development ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Cardiac Development ◽  
Model Organism ◽  
The United States ◽  
Therapeutic Interventions ◽  
Chip Sequencing ◽  
Active Transcription

Heart disease is the leading cause of death in the United States and worldwide. Understanding the molecular mechanisms of cardiac development and regeneration will improve diagnostic and therapeutic interventions against heart disease. In this direction, zebrafish is an excellent model because several processes of zebrafish heart development are largely conserved in humans, and zebrafish has several advantages as a model organism. Zebrafish transcriptomic profiles undergo alterations during different stages of cardiac development and regeneration which are revealed by RNA-sequencing. ChIP-sequencing has detected genome-wide occupancy of histone post-translational modifications that epigenetically regulate gene expression and identified a locus with enhancer-like characteristics. ATAC-sequencing has identified active enhancers in cardiac progenitor cells during early developmental stages which overlap with occupancy of histone modifications of active transcription as determined by ChIP-sequencing. CRISPR-mediated editing of the zebrafish genome shows how chromatin modifiers and DNA-binding proteins regulate heart development, in association with crucial signaling pathways. Hence, more studies in this direction are essential to improve human health because they answer fundamental questions on cardiac development and regeneration, their differences, and why zebrafish hearts regenerate upon injury, unlike humans. This review focuses on some of the latest studies using state-of-the-art technology enabled by the elegant yet simple zebrafish.

scholarly journals Circadian Mechanisms: Cardiac Ion Channel Remodeling and Arrhythmias

2021 ◽  
Vol 11 ◽  
Author(s):  
Joyce Bernardi ◽  
Kelly A. Aromolaran ◽  
Hua Zhu ◽  
Ademuyiwa S. Aromolaran
Keyword(s):  
Heart Failure ◽  
Circadian Rhythms ◽  
Molecular Mechanisms ◽  
Normal Sinus Rhythm ◽  
Critical Role ◽  
The United States ◽  
Therapeutic Interventions ◽  
Cellular Mechanisms ◽  
Normal Sinus ◽  
Obesity And Diabetes

Circadian rhythms are involved in many physiological and pathological processes in different tissues, including the heart. Circadian rhythms play a critical role in adverse cardiac function with implications for heart failure and sudden cardiac death, highlighting a significant contribution of circadian mechanisms to normal sinus rhythm in health and disease. Cardiac arrhythmias are a leading cause of morbidity and mortality in patients with heart failure and likely cause ∼250,000 deaths annually in the United States alone; however, the molecular mechanisms are poorly understood. This suggests the need to improve our current understanding of the underlying molecular mechanisms that increase vulnerability to arrhythmias. Obesity and its associated pathologies, including diabetes, have emerged as dangerous disease conditions that predispose to adverse cardiac electrical remodeling leading to fatal arrhythmias. The increasing epidemic of obesity and diabetes suggests vulnerability to arrhythmias will remain high in patients. An important objective would be to identify novel and unappreciated cellular mechanisms or signaling pathways that modulate obesity and/or diabetes. In this review we discuss circadian rhythms control of metabolic and environmental cues, cardiac ion channels, and mechanisms that predispose to supraventricular and ventricular arrhythmias including hormonal signaling and the autonomic nervous system, and how understanding their functional interplay may help to inform the development and optimization of effective clinical and therapeutic interventions with implications for chronotherapy.

The zebrafish as a model for cardiac development and regeneration

2018 ◽  
Author(s):  
Bill Chaudhry ◽  
José Luis de la Pompa ◽  
Nadia Mercader
Keyword(s):  
Heart Development ◽  
Cardiac Development ◽  
Model Organism ◽  
Laboratory Model ◽  
Developmental Studies ◽  
Sequencing Technologies ◽  
Technological Advances ◽  
The Common ◽  
Zebrafish Heart

The zebrafish has become an established laboratory model for developmental studies and is increasingly used to model aspects of human development and disease. However, reviewers and grant funding bodies continue to speculate on the utility of this Himalayan minnow. In this chapter we explain the similarities and differences between the heart from this distantly related vertebrate and the mammalian heart, in order to reveal the common fundamental processes and to prevent misleading extrapolations. We provide an overview of zebrafish including their husbandry, development, peculiarities of their genome, and technological advances, which make them a highly tractable laboratory model for heart development and disease. We discuss the controversies around morphants and mutants, and relate the development and structures of the zebrafish heart to mammalian counterparts. Finally, we give an overview of regeneration in the zebrafish heart and speculate on the role of the model organism in next-generation sequencing technologies.

scholarly journals Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
David Kung-Chun Chiu ◽  
Aki Pui-Wah Tse ◽  
Cheuk-Ting Law ◽  
Iris Ming-Jing Xu ◽  
Derek Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mitochondrial Biogenesis ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Notch Pathway ◽  
Redox Balance ◽  
Therapeutic Interventions ◽  
Luciferase Reporter ◽  
Mitochondrial Activity ◽  
Chip Sequencing

AbstractHypoxia is commonly found in cancers. Hypoxia, due to the lack of oxygen (O2) as the electron recipient, causes inefficient electron transfer through the electron transport chain at the mitochondria leading to accumulation of reactive oxygen species (ROS) which could create irreversible cellular damages. Through hypoxia-inducible factor 1 (HIF-1) which elicits various molecular events, cells are able to overcome low O2. Knowledge about the new molecular mechanisms governed by HIF-1 is important for new therapeutic interventions targeting hypoxic tumors. Using hepatocellular carcinoma (HCC) as a model, we revealed that the HIF-1 and the Notch signaling pathways cross-talk to control mitochondrial biogenesis of cancer cells to maintain REDOX balance. From transcriptome sequencing, we found that HEY1, a transcriptional repressor, in the NOTCH pathway was consistently induced by hypoxia in HCC cell lines. We identified a strong hypoxia response element (HRE) in HEY1 by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Transcriptome and ChIP sequencing further identified PINK1, a gene essential for mitochondrial biogenesis, as a novel transcriptional target of HEY1. HCC cells with HEY1 knockdown re-expressed PINK1. HEY1 and PINK1 expressions inversely correlated in human HCC samples. Overexpression of HEY1 and under-expression of PINK1 were detected in human HCC and associated with poor clinical outcomes. Functionally, we found that overexpression of HEY1 or knockdown of PINK1 consistently reduced mitochondrial cristae, mitochondrial mass, oxidative stress level, and increased HCC growth.

scholarly journals Evaluation of Cosmetic Properties of Natural Ingredients in the Trás-os-Montes area: a PhD Project

2021 ◽  
Author(s):  
Sara Gonçalves ◽  
Isabel Gaivão
Keyword(s):  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Human Lymphocytes ◽  
Ecological Impact ◽  
Model Organism ◽  
The Body ◽  
In Vivo Model ◽  
Dna Integrity ◽  
The European Union

The term cosmetics refers to a product applied to the body for the purpose of beautifying, cleansing or improving appearance and enhancing attractive features. The natural cosmetics market has grown since the consumer took consciousness of the concept of natural-based ingredients. A great number of cosmetics have noxious and chemically-potent substances and have an ecological impact on the environment. A study performed by the Danish Council THINK Chemicalsfound that in total 65 chemicals of concern were found in 39 products. This means consumers are exposed to these chemicals, perhaps in a daily basis. They also found that three products contained illegal ingredients in the European Union. Thus, the use of natural and organic cosmetics becomes increasingly important. This requires a strong investigation into the benefits that fruits and plants can bring to health. The PhD project will focus on four natural ingredients common in the Trás-os-Montes area: almond (Prunus dulcis), elderberry (Sambucus nigra), olive (Olea europaea) and grapes (Vitis vinifera). The general purpose of this PhD project is to evaluate the cosmetic properties of the natural ingredients towards the DNA integrity promotion. Additionally, it is intended to evaluate genoprotection, longevity and prolificacy of the natural ingredients in Drosophila melanogaster. The short life cycle, the distinct developmental stages, the availability of various tools and reagents, known genome sequence and the physiological similarity of Drosophila with humans make them an excellent in vivo model organism to rapidly test toxicity in whole organism and elucidate the molecular mechanisms underlying the toxicity. The natural product with the best result will be used to evaluate genoprotection in human lymphocytes. These are used as a surrogate tissue, as they are easily obtained, in large numbers, do not require cell culture, are diploids and are almost all in the same phase of the cell cycle. This project is in an initial phase and lacks results, which will be available along this year.

scholarly journals CFTR deficiency causes cardiac dysplasia during zebrafish embryogenesis and is associated with dilated cardiomyopathy

2020 ◽  
Author(s):  
Yanyan Liu ◽  
Ziyuan Lin ◽  
Mingfeng Liu ◽  
Huijuan Liao ◽  
Yan Chen ◽  
...  
Keyword(s):  
Heart Disease ◽  
Dilated Cardiomyopathy ◽  
Heart Development ◽  
Cardiac Development ◽  
Myocardial Dysfunction ◽  
Primary Defect ◽  
Zebrafish Model ◽  
Human Heart Failure ◽  
Stage Of Development

Abstract Background: Mutations in the CFTR gene cause cystic fibrosis (CF) with myocardial dysfunction. However, it remains unknown whether CF-related heart disease is a secondary effect of pulmonary disease, or an intrinsic primary defect in the CF heart. Results: Here, we used a zebrafish model, which lacks lung tissue, to investigate the role of CFTR in cardiogenesis during embryonic development. Our findings demonstrate that a loss of CFTR impairs cardiac development from the cardiac progenitor stage of heart development, resulting in cardiac looping defects, a dilated atrium, pericardial edema, and a decrease in heart rate. Furthermore, we found that cardiac development is perturbed in wild type embryos treated with a gating specific Cftr channel inhibitor, CFTRinh-172, at the blastula stage of development, but not with treatment at later stages. Gene expression analysis of blastulas indicated that transcript levels, including mRNAs associated with cardiovascular diseases, were significantly altered in embryos derived from cftr mutants relative to controls. To evaluate the role of CFTR in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found that CFTR containing I556V mutation, which causes a channel defect, is associated with the disease. Similar to well-studied channel-defective CFTR mutants, CFTR I556V mRNA failed to restore cardiac dysplasia in mutant embryos. Conclusions: The present study reveals an important role for the CFTR ion channel in regulating cardiac development during early embryogenesis, supporting the hypothesis that CF-related heart disease results from an intrinsic primary defect in the CF heart.

scholarly journals Heart failure in single right ventricle congenital heart disease: physiological and molecular considerations

2020 ◽  
Vol 318 (4) ◽  
pp. H947-H965 ◽  
Author(s):  
Anastacia M. Garcia ◽  
Jonathan-Thomas Beatty ◽  
Stephanie J. Nakano
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
Right Ventricle ◽  
Congenital Heart ◽  
Molecular Mechanisms ◽  
Therapeutic Interventions ◽  
Anatomy And Physiology ◽  
Molecular Alterations

Because of remarkable surgical and medical advances over the past several decades, there are growing numbers of infants and children living with single ventricle congenital heart disease (SV), where there is only one functional cardiac pumping chamber. Nevertheless, cardiac dysfunction (and ultimately heart failure) is a common complication in the SV population, and pharmacological heart failure therapies have largely been ineffective in mitigating the need for heart transplantation. Given that there are several inherent risk factors for ventricular dysfunction in the setting of SV in addition to probable differences in molecular adaptations to heart failure between children and adults, it is perhaps not surprising that extrapolated adult heart failure medications have had limited benefit in children with SV heart failure. Further investigations into the molecular mechanisms involved in pediatric SV heart failure may assist with risk stratification as well as development of targeted, efficacious therapies specific to this patient population. In this review, we present a brief overview of SV anatomy and physiology, with a focus on patients with a single morphological right ventricle requiring staged surgical palliation. Additionally, we discuss outcomes in the current era, risk factors associated with the progression to heart failure, present state of knowledge regarding molecular alterations in end-stage SV heart failure, and current therapeutic interventions. Potential avenues for improving SV outcomes, including identification of biomarkers of heart failure progression, implications of personalized medicine and stem cell-derived therapies, and applications of novel models of SV disease, are proposed as future directions.

scholarly journals SRSF3 is a key regulator of epicardial formation

2021 ◽  
Author(s):  
Irina-Elena Lupu ◽  
Andia Nicole Redpath ◽  
Nicola Smart
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Cellular Proliferation ◽  
Rna Binding ◽  
Cardiac Development ◽  
Cardiac Fibroblasts ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Epicardial Layer

The epicardium is a fundamental regulator of cardiac development, functioning to secrete essential growth factors and to produce epicardium-derived cells (EPDCs) that contribute most coronary vascular smooth muscle cells and cardiac fibroblasts. The molecular mechanisms that control epicardial formation and proliferation have not been fully elucidated. In this study, we found that the RNA-binding protein SRSF3 is highly expressed in the proepicardium and later in the epicardial layer during heart development. Deletion of Srsf3 from the murine proepicardium using the Tg(Gata5-Cre) or embryonic day (E) 8.5 induction of Wt1CreERT2 led to proliferative arrest and impaired epithelial-to-mesenchymal transition (EMT), which prevented proper formation and function of the epicardial layer. Induction of Srsf3 deletion with the Wt1CreERT2 after the proepicardial stage resulted in impaired EPDC formation and epicardial proliferation at E13.5. Single-cell RNA-sequencing showed SRSF3-depleted epicardial cells were removed by E15.5 and the remaining non-recombined cells became hyperproliferative and compensated for the loss via up-regulation of Srsf3. This research identifies SRSF3 as a master regulator of cellular proliferation in epicardial cells.

scholarly journals YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes

2021 ◽  
Vol 22 (13) ◽  
pp. 6649
Author(s):  
Yunan Gao ◽  
Yan Sun ◽  
Adife Gulhan Ercan-Sencicek ◽  
Justin S. King ◽  
Brynn N. Akerberg ◽  
...  
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Heart Diseases ◽  
Luciferase Reporter ◽  
Binding Motif ◽  
Expression Levels ◽  
Genomic Regions

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, Tlr8, and Tlr9 in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac Tlr3, Tlr7, Tlr8, and Tlr9 increased with age between neonatal and adult developmental stages, whereas the expression of Tlr5 decreased with age. Furthermore, pathological stress increased the expression levels of Tlr2, Tlr4, Tlr5, Tlr7, Tlr8, and Tlr9. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, and Tlr9. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near Tlr4 transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes.

scholarly journals A reference map of murine cardiac transcription factor chromatin occupancy identifies dynamic and conserved enhancers

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Brynn N. Akerberg ◽  
Fei Gu ◽  
Nathan J. VanDusen ◽  
Xiaoran Zhang ◽  
Rui Dong ◽  
...  
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Transcriptional Regulatory Network ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Mouse Heart ◽  
Transcriptional Enhancer ◽  
Enhancer Activity

Abstract Mapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs. Here we use biotinylated knockin alleles of seven key cardiac TFs (GATA4, NKX2-5, MEF2A, MEF2C, SRF, TBX5, TEAD1) to sensitively and reproducibly map their genome-wide occupancy in the fetal and adult mouse heart. These maps show that TF occupancy is dynamic between developmental stages and that multiple TFs often collaboratively occupy the same chromatin region through indirect cooperativity. Multi-TF regions exhibit features of functional regulatory elements, including evolutionary conservation, chromatin accessibility, and activity in transcriptional enhancer assays. H3K27ac, a feature of many enhancers, incompletely overlaps multi-TF regions, and multi-TF regions lacking H3K27ac retain conservation and enhancer activity. TEAD1 is a core component of the cardiac transcriptional network, co-occupying cardiac regulatory regions and controlling cardiomyocyte-specific gene functions. Our study provides a resource for deciphering the cardiac transcriptional regulatory network and gaining insights into the molecular mechanisms governing heart development.

scholarly journals Epigenetics and Mechanobiology in Heart Development and Congenital Heart Disease

Diseases ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 52 ◽  
Author(s):  
Jarrell ◽  
Lennon ◽  
Jacot
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Heart Development ◽  
Congenital Heart ◽  
Normal Development ◽  
Heart Defects ◽  
The United States ◽  
Complex Interactions ◽  
Epigenetic Biomarkers ◽  
Multiple Cell

: Congenital heart disease (CHD) is the most common birth defect worldwide and the number one killer of live-born infants in the United States. Heart development occurs early in embryogenesis and involves complex interactions between multiple cell populations, limiting the understanding and consequent treatment of CHD. Furthermore, genome sequencing has largely failed to predict or yield therapeutics for CHD. In addition to the underlying genome, epigenetics and mechanobiology both drive heart development. A growing body of evidence implicates the aberrant regulation of these two extra-genomic systems in the pathogenesis of CHD. In this review, we describe the stages of human heart development and the heart defects known to manifest at each stage. Next, we discuss the distinct and overlapping roles of epigenetics and mechanobiology in normal development and in the pathogenesis of CHD. Finally, we highlight recent advances in the identification of novel epigenetic biomarkers and environmental risk factors that may be useful for improved diagnosis and further elucidation of CHD etiology.

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