Abstract 240: Asb2-dependent Proteolysis of the Cytoskeleton Directs Cardiac Development and Disease

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Abir Yamak ◽  
Dongjian Hu ◽  
Ibrahim J Domian
Keyword(s):  
Heart Development ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Ubiquitin Proteasome System ◽  
Actin Binding ◽  
Human Cardiomyocytes ◽  
Morphological Defects ◽  
Pericardial Edema ◽  
Induced Pluripotent

Congenital heart diseases (CHDs) account for 25% of birth defects and are major risk factors for adult cardiovascular problems. Partial disease penetrance is seen even in autosomal dominant disorders and genotype/phenotype correlations remain a clinical challenge; thus, the need to understand different regulators of cardiac formation. The Ubiquitin-Proteasome System (UPS) is important in controlling protein turnover during organ development but its role in the mammalian heart remains ambiguous. We have identified a specificity subunit of ubiquitin-mediated proteolysis (Asb2) as being specific for the cardiac myogenic lineage. Asb2 was previously shown to regulate hematopoietic and skeletal muscle cell differentiation through targeting filamin proteins (FlnA, B and C), actin-binding proteins important for cytoskeleton stabilization. In our present study, we show that Asb2 is markedly enriched in myocardial progenitor cells and cardiomyocytes. To investigate the role of Asb2 and UPS dependent proteolysis in heart development, we generated two cardiac-specific murine knockouts (KOs): Nkx Cre .Asb2 -/- and Mef2c Cre .Asb2 -/- (deleting Asb2 in early cardiomyocyte progenitors and anterior heart field progenitors, respectively). Both KOs are embryonic lethal with pericardial edema. We used tissue clarifying and confocal microscopy to define the morphological defects of the Asb2 null heart. Moreover, we found that FlnA is overexpressed in the hearts of these mice and its deletion therein partially rescues their lethality. In addition, using transcriptomic analysis on Asb2-null e9.5 hearts, we identified novel potential Asb2 targets in the heart. Finally, to understand the role of Asb2 in the differentiation and function of human cardiomyocytes, we used CRISPR/Cas9 genome editing technique to generate Asb2-null human induced pluripotent stem cells. Collectively, our study provides a novel mechanistic understanding of the role of the UPS proteasome in cardiac development, myocardial function, and disease pathogenesis. Given recent interests in both the UPS and the cytoskeleton as therapeutic targets, our study provides an innovative platform for the development of pharmacotherapy for cardiac disease.

Abstract 257: Clonal Analysis Of Multipotent Cardiovascular Progenitors That Generate Cardiomyocytes During Development

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Konstantina Ioanna Sereti ◽  
Paniz Kamran Rashani ◽  
Peng Zhao ◽  
Reza Ardehali
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Cardiac Development ◽  
Clonal Analysis ◽  
Cardiac Cells ◽  
Single Cell Level ◽  
Reporter System ◽  
Cell Level ◽  
Cardiac Progenitors

It has been proposed that cardiac development in lower vertebrates is driven by the proliferation of cardiomyocytes. Similarly, cycling myocytes have been suggested to direct cardiac regeneration in neonatal mice after injury. Although, the role of cardiomyocyte proliferation in cardiac tissue generation during development has been well documented, the extent of this contribution as well as the role of other cell types, such as progenitor cells, still remains controversial. Here we used a novel stochastic four-color Cre-dependent reporter system (Rainbow) that allows labeling at a single cell level and retrospective analysis of the progeny. Cardiac progenitors expressing Mesp1 or Nkx2.5 were shown to be a source of cardiomyocytes during embryonic development while the onset of αMHC expression marked the developmental stage where the capacity of cardiac cells to proliferate diminishes significantly. Through direct clonal analysis we provide strong evidence supporting that cardiac progenitors, as opposed to mature cardiomyocytes, are the main source of cardiomyocytes during cardiac development. Moreover, we have identified quadri-, tri-, bi, and uni-potent progenitors that at a single cell level can generate cardiomyocytes, fibroblasts, endothelial and smooth muscle cells. Although existing cardiomyocytes undergo limited proliferation, our data indicates that it is mainly the progenitors that contribute to heart development. Furthermore, we show that the limited proliferation capacity of cardiomyocytes observed during normal development was enhanced following neonatal cardiac injury allowing almost complete regeneration of the scared tissue. However, this ability was largely absent in adult injured hearts. Detailed characterization of dividing cardiomyocytes and proliferating progenitors would greatly benefit the development of novel therapeutic options for cardiovascular diseases.

scholarly journals ISCA1 Deficiency Induces Iron Metabolism Disorder and Myocardial Oncosis in Rat

2021 ◽  
Author(s):  
Yahao Ling ◽  
Xinlan Yang ◽  
Xu Zhang ◽  
Feifei Guan ◽  
Xiaolong Qi ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Iron Metabolism ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Pathological Process ◽  
Metabolism Disorder ◽  
Abnormal Metabolism ◽  
Validation Experiments

Abstract The effects of multiple mitochondrial dysfunction (MMD) on heart, a highly mitochondria-dependent tissue, is still unclear. This study was the first to verify the effect of ISCA1 gene deficiency, which has been shown to cause multiple mitochondrial dysfunction syndromes type 5 (MMDS5), on cardiac development in vivo, that is cardiomyocytes suffer from energy shortage due to abnormal metabolism of iron ion, which leads to oncosis and eventually HF and body death. Subsequently, we determine a new interacting molecule for ISCA1, six-transmembrane epithelial antigen of prostate 3 (STEAP3), which acts as a reductase in the reduction of Fe3+ to Fe2+. Forward and reverse validation experiments demonstrated that STEAP3 plays an important role in iron metabolism and energy generation impairment induced by ISCA1 deficiency. This result provides theoretical basis for understanding of MMDS pathogenesis, especially on heart development and the pathological process of heart diseases, and finally provides new clues for searching of clinical therapeutic targets.

At the heart of programming: the role of micro-RNAs

2018 ◽  
Vol 9 (6) ◽  
pp. 615-631 ◽  
Author(s):  
B. Siddeek ◽  
C. Mauduit ◽  
C. Yzydorczyk ◽  
M. Benahmed ◽  
U. Simeoni
Keyword(s):  
Heart Development ◽  
Disease Risk ◽  
Heart Diseases ◽  
Underlying Mechanism ◽  
Micro Rna ◽  
Environmental Challenges ◽  
Micro Rnas ◽  
Heart Functions ◽  
Heart Disease Risk

AbstractEpidemiological and experimental observations tend to prove that environment, lifestyle or nutritional challenges influence heart functions together with genetic factors. Furthermore, when occurring during sensitive windows of heart development, these environmental challenges can induce an ‘altered programming’ of heart development and shape the future heart disease risk. In the etiology of heart diseases driven by environmental challenges, epigenetics has been highlighted as an underlying mechanism, constituting a bridge between environment and heart health. In particular, micro-RNAs which are involved in each step of heart development and functions seem to play a crucial role in the unfavorable programming of heart diseases. This review describes the latest advances in micro-RNA research in heart diseases driven by early exposure to challenges and discusses the use of micro-RNAs as potential targets in the reversal of the pathophysiology.

Abstract 052: Epicardial-derived Adrenomedullin Drives Cardiac Hyperplasia During Embryogenesis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sarah E Wetzel-Strong ◽  
Manyu Li ◽  
Toshio Nishikimi ◽  
Kathleen M Caron
Keyword(s):  
Embryonic Development ◽  
Heart Development ◽  
Cardiac Development ◽  
Lymphatic Vessels ◽  
Heart Weight ◽  
Cardiovascular Development ◽  
Proliferating Cells ◽  
Over Expression ◽  
Knockout Animals

The multi-functional peptide adrenomedullin ( Adm = gene, AM = protein) plays important roles in embryonic development and disease. Previous studies demonstrated that Adm knockout mice die at embryonic day 13.5 with small, disorganized hearts and hypoplastic lymphatic vessels, highlighting the importance of this peptide in normal cardiovascular development. Since Adm knockout animals are embryonic lethal, our goal was to generate and characterize a novel model of Adm over-expression to study the role of Adm during development and disease processes. Through gene targeting techniques, we generated a novel mouse model of Adm over-expression, abbreviated as Adm hi/hi . When we assessed gene expression of Adm from 10 different tissues, we found Adm hi/hi mice express 3- to 15-fold more Adm than wildtype littermates. Additionally, peptide levels of AM in lung and kidney, as well as circulating plasma levels of AM were elevated 3-fold over wildtype mice, indicating a functional increase in AM. Our initial analysis revealed that adult Adm hi/hi mice have larger heart weight to body weight ratios than wildtype littermates (4.93±0.23 vs. 5.96±0.29, n = 11-12). We found that compared to wildtype, Adm hi/hi embryos have more proliferating cells during heart development (14.46±1.11 vs. 31.97±2.84, n=4), indicating that hyperplasia drives Adm hi/hi heart enlargement. By crossing the Adm hi/hi line to different tissue-specific Cre lines, we were able to excise the stabilizing bovine growth hormone 3’UTR, thereby returning Adm expression levels back to wildtype in cells with active Cre recombinase. Using this approach, we identified the epicardium as a major source of AM during cardiac development. In conclusion, we found that AM derived primarily from the epicardium drives cardiac hyperplasia during embryonic development resulting in persistent, enlarged hearts of adult Adm hi/hi mice. Since our Adm hi/hi mice recapitulate the 3-fold plasma elevation of AM observed during human disease, this mouse line will be a useful tool for studying the role of elevated AM during disease.

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.

The Role of Shear Stress on ET-1, KLF2, and NOS-3 Expression in the Developing Cardiovascular System of Chicken Embryos in a Venous Ligation Model

Physiology ◽  
2007 ◽  
Vol 22 (6) ◽  
pp. 380-389 ◽  
Author(s):  
Bianca C. W. Groenendijk ◽  
Kim Van der Heiden ◽  
Beerend P. Hierck ◽  
Robert E. Poelmann
Keyword(s):  
Shear Stress ◽  
Heart Development ◽  
Cardiac Development ◽  
Background Information ◽  
Endothelial Shear Stress ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Cardiovascular Anomalies ◽  
Chicken Model

In this review, the role of wall shear stress in the chicken embryonic heart is analyzed to determine its effect on cardiac development through regulating gene expression. Therefore, background information is provided for fluid dynamics, normal chicken and human heart development, cardiac malformations, cardiac and vitelline blood flow, and a chicken model to induce cardiovascular anomalies. A set of endothelial shear stress-responsive genes coding for endothelin-1 (ET-1), lung Krüppel-like factor (LKLF/KLF2), and endothelial nitric oxide synthase (eNOS/NOS-3) are active in development and are specifically addressed.

scholarly journals The role of KMT2D and KDM6A in cardiac development: A cross-species analysis in humans, mice, and zebrafish

2020 ◽  
Author(s):  
Rwik Sen ◽  
Ezra Lencer ◽  
Elizabeth A. Geiger ◽  
Kenneth L. Jones ◽  
Tamim H. Shaikh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Development ◽  
Target Genes ◽  
Cardiac Development ◽  
Heart Defects ◽  
Neural Crest Cell ◽  
Kabuki Syndrome ◽  
Rna Seq ◽  
Wide Range

AbstractCongenital Heart Defects (CHDs) are the most common form of birth defects, observed in 4-10/1000 live births. CHDs result in a wide range of structural and functional abnormalities of the heart which significantly affect quality of life and mortality. CHDs are often seen in patients with mutations in epigenetic regulators of gene expression, like the genes implicated in Kabuki syndrome – KMT2D and KDM6A, which play important roles in normal heart development and function. Here, we examined the role of two epigenetic histone modifying enzymes, KMT2D and KDM6A, in the expression of genes associated with early heart and neural crest cell (NCC) development. Using CRISPR/Cas9 mediated mutagenesis of kmt2d, kdm6a and kdm6al in zebrafish, we show cardiac and NCC gene expression is reduced, which correspond to affected cardiac morphology and reduced heart rates. To translate our results to a human pathophysiological context and compare transcriptomic targets of KMT2D and KDM6A across species, we performed RNA sequencing (seq) of lymphoblastoid cells from Kabuki Syndrome patients carrying mutations in KMT2D and KDM6A. We compared the human RNA-seq datasets with RNA-seq datasets obtained from mouse and zebrafish. Our comparative interspecies analysis revealed common targets of KMT2D and KDM6A, which are shared between species, and these target genes are reduced in expression in the zebrafish mutants. Taken together, our results show that KMT2D and KDM6A regulate common and unique genes across humans, mice, and zebrafish for early cardiac and overall development that can contribute to the understanding of epigenetic dysregulation in CHDs.

The role of the neural crest in cardiac development

2018 ◽  
Author(s):  
Laura A. Dyer ◽  
Margaret L. Kirby
Keyword(s):  
Neural Crest ◽  
Neural Tube ◽  
Heart Development ◽  
Cardiac Development ◽  
Signalling Pathways ◽  
Pharyngeal Arches ◽  
Cardiac Neural Crest ◽  
Final Destination ◽  
Dorsal Neural Tube

The cardiac neural crest (CNC) plays pivotal roles in numerous steps of cardiac development. Every aspect of the CNC cell’s lifespan is highly orchestrated, from its induction in the dorsal neural tube to its migration to its differentiation at its final destination. During migration, CNC cells are affected by their environment and simultaneously modulate the extra-cellular milieu through which they migrate. In the pharyngeal arches, CNC cells repattern the originally symmetrical arch arteries, producing the great arteries. Because the cardiac neural crest is essential for many aspects of heart development, it is unsurprising that human CNC-related syndromes have severe phenotypes. This chapter describes how CNC cells are formed and contribute to their final destinations. Essential signalling pathways are presented in the context of CNC development, and CNC-related syndromes are included to highlight this population’s broad importance during development.

scholarly journals The Long Non-Coding RNA SNHG1 Attenuates Cell Apoptosis by Regulating miR-195 and BCL2-Like Protein 2 in Human Cardiomyocytes

2018 ◽  
Vol 50 (3) ◽  
pp. 1029-1040 ◽  
Author(s):  
Ning Zhang ◽  
Xin Meng ◽  
Lijun Mei ◽  
Jian Hu ◽  
Chedong Zhao ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Heart Diseases ◽  
Cardiomyocyte Apoptosis ◽  
Luciferase Reporter ◽  
H2o2 Treatment ◽  
Human Cardiomyocytes

Background/Aims: Long non-coding RNAs (lncRNAs) are theorized to play key roles in the development of heart diseases. However, the role of lncRNAs in cardiomyocyte apoptosis is largely unknown. The present study examined the role of lncRNA SNHG1 in the human cardiomyocytes (HCMs) apoptosis and explored the underlying molecular mechanisms. Methods: SNHG1, miR-195 and mRNA expression was detected by qRT-PCR; protein level was determined by western blot; cell viability was detected by MTT assay; cell apoptosis was evaluated by flow cytometry and caspase-3 activity assay; the interaction between SNHG1 and miR195 was examined by using luciferase reporter assay. Results: Hydrogen peroxide (H2O2) treatment significantly suppressed cell viability and increased cell apoptotic rate and caspase-3 activity in HCMs. Overexpression of SNHG1 attenuated the effects of H2O2 on HCMs viability and apoptosis; while SNHG1 exerted the opposite effects. SNHG1 was found to sponge miR-195 and suppress the expression of miR-195 in HCMs. Overexpression of miR-195 suppressed cell viability and induced apoptosis in HCMs, and miR-195 was found to negatively regulate the expression of BCL-2 like protein 2 (BCL2L2) via targeting its 3’ untranslated region. Overexpression of BCL2L2 partially reversed the effects of miR-195 overexpression on cell viability and cell apoptosis of HCMs. MiR-195 overexpression or BCL2L2 knockdown attenuated the effects of SNHG1 overexpression on cell viability, cell apoptosis and protein levels of cleaved caspase-3, cleaved caspase-9 and Bax in H2O2-treated HCMs. Conclusion: Our results suggest a novel SNHG1/miR-195/BCL2L2 axis in the regulation of cardiomyocyte apoptosis. Modulation of SNHG1 may represent a novel strategy to treat cardiomyocyte apoptosis-related heart diseases.

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