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Transcriptional Regulation of Cardiac Development and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 33530

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Institute of Biology Valrose, University of Nice Sophia Antipolis, 06107 Nice, France
Interests: vessel formation in development and disease; transcriptional control; epigenetics; cardiovascular disease
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Dear Colleagues,

The heart is the first organ that forms and functions during embryonic development; and it must continue to work without interruption throughout one’s lifetime. In early embryonic development, the cardiac crescent contains progenitor cells of the first and second heart fields, which will develop mainly into the left ventricle/proportion of atria and the right ventricle/outflow tract/atria, respectively. The contribution of epicardial, endocardial, sinus venosus, and hematopoietic-derived cells to the heart is still controversial. Although some important transcriptional regulators of cardiac development have been identified, e.g., Gata transcription factors, Hand 1/2, TBX5, NKX2-5, MEF2, SRF, Wt1, their interactions are complex, and the transcriptional targets are not fully investigated. Many previous studies focused globally on cardiomyocyte development, but relatively little is known regarding how different cardiomyocyte subpopulations and other cells types contributing to the heart, i.e., fibroblasts, endothelial, smooth muscle, epicardial, endocardial, and immune cells, are specified.

In contrast to lower vertebrates, cardiac development is finished in mammals soon after birth, and regeneration capacity becomes extremely limited. Nevertheless, cardiomyocyte proliferation is a prerequisite for cardiac regeneration in the adult. Several transgenic mouse models with increased cardiomyocyte proliferation and improved recovery after cardiac injury have been reported. However, translation to clinical practice is limited for ethical reasons and the risk of tumor development. In zebrafish, lineage tracing studies after injury showed that newly formed cardiac cells are derived from pre-existing de-differentiating cardiomyocytes instead of a pool of cardiac progenitors. In neonatal mice, a subset of cardiomyocytes seems to be in a permissive (embryonic) state, which allows re-entry in the cell cycle and repair after injury. Thus, it would be of high interest to identify the transcriptional signature of this subset of cells to direct cardiac repair in the future.

In addition to the evident problem in stimulating cardiomyocyte proliferation for repair after injury, several additional points have to be considered. Increased cardiomyocyte repair needs additional adequate blood supply (angiogenesis) for proper cardiac function. Damaged cells must be removed by immune cells and the tissue temporarily stabilized by a fibrotic response. However, excessive or prolonged immune and fibroblast activation will result in additional damage and impaired function due to increased tissue stiffness. Thus, for efficient cardiac repair after injury, not only cardiomyocyte proliferation, but also adequate timing of angiogenesis, immune, and fibrotic response must be well orchestrated.

This Special Issue of the International Journal of Molecular Sciences will bring together the most recent advances in understanding the various aspects of the transcriptional regulation of cardiac development and disease, from basic science to applied therapeutic approaches, and will provide new insights into the complex transcriptional regulation of cardiac development, disease, regeneration, and the different cell types involved.

Dr. Nicole Wagner
Prof. Dr. Kay-Dietrich Wagner
Guest Editors

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Published Papers (11 papers)

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Editorial

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4 pages, 197 KiB  
Editorial
Transcriptional Regulation of Cardiac Development and Disease
by Nicole Wagner and Kay-Dietrich Wagner
Int. J. Mol. Sci. 2022, 23(6), 2945; https://doi.org/10.3390/ijms23062945 - 09 Mar 2022
Cited by 1 | Viewed by 1257
Abstract
The heart, which is the first organ to develop in the embryo, is indispensable for vital functions throughout life [...] Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)

Research

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24 pages, 2118 KiB  
Article
Transcriptomic Signatures of End-Stage Human Dilated Cardiomyopathy Hearts with and without Left Ventricular Assist Device Support
by Mihir Parikh, Saumya Shah, Ratnadeep Basu, Konrad S. Famulski, Daniel Kim, John C. Mullen, Philip F. Halloran and Gavin Y. Oudit
Int. J. Mol. Sci. 2022, 23(4), 2050; https://doi.org/10.3390/ijms23042050 - 12 Feb 2022
Cited by 4 | Viewed by 2386
Abstract
Left ventricular assist device (LVAD) use in patients with dilated cardiomyopathy (DCM) can lead to a differential response in the LV and right ventricle (RV), and RV failure remains the most common complication post-LVAD insertion. We assessed transcriptomic signatures in end-stage DCM, and [...] Read more.
Left ventricular assist device (LVAD) use in patients with dilated cardiomyopathy (DCM) can lead to a differential response in the LV and right ventricle (RV), and RV failure remains the most common complication post-LVAD insertion. We assessed transcriptomic signatures in end-stage DCM, and evaluated changes in gene expression (mRNA) and regulation (microRNA/miRNA) following LVAD. LV and RV free-wall tissues were collected from end-stage DCM hearts with (n = 8) and without LVAD (n = 8). Non-failing control tissues were collected from donated hearts (n = 6). Gene expression (for mRNAs/miRNAs) was determined using microarrays. Our results demonstrate that immune response, oxygen homeostasis, and cellular physiological processes were the most enriched pathways among differentially expressed genes in both ventricles of end-stage DCM hearts. LV genes involved in circadian rhythm, muscle contraction, cellular hypertrophy, and extracellular matrix (ECM) remodelling were differentially expressed. In the RV, genes related to the apelin signalling pathway were affected. Following LVAD use, immune response genes improved in both ventricles; oxygen homeostasis and ECM remodelling genes improved in the LV and, four miRNAs normalized. We conclude that LVAD reduced the expression and induced additional transcriptomic changes of various mRNAs and miRNAs as an integral component of the reverse ventricular remodelling in a chamber-specific manner. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
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25 pages, 34151 KiB  
Article
Cardiomyogenic Differentiation Potential of Human Dilated Myocardium-Derived Mesenchymal Stem/Stromal Cells: The Impact of HDAC Inhibitor SAHA and Biomimetic Matrices
by Rokas Miksiunas, Ruta Aldonyte, Agne Vailionyte, Tadas Jelinskas, Romuald Eimont, Gintare Stankeviciene, Vytautas Cepla, Ramunas Valiokas, Kestutis Rucinskas, Vilius Janusauskas, Siegfried Labeit and Daiva Bironaite
Int. J. Mol. Sci. 2021, 22(23), 12702; https://doi.org/10.3390/ijms222312702 - 24 Nov 2021
Cited by 6 | Viewed by 2358
Abstract
Dilated cardiomyopathy (DCM) is the most common type of nonischemic cardiomyopathy characterized by left ventricular or biventricular dilation and impaired contraction leading to heart failure and even patients’ death. Therefore, it is important to search for new cardiac tissue regenerating tools. Human mesenchymal [...] Read more.
Dilated cardiomyopathy (DCM) is the most common type of nonischemic cardiomyopathy characterized by left ventricular or biventricular dilation and impaired contraction leading to heart failure and even patients’ death. Therefore, it is important to search for new cardiac tissue regenerating tools. Human mesenchymal stem/stromal cells (hmMSCs) were isolated from post-surgery healthy and DCM myocardial biopsies and their differentiation to the cardiomyogenic direction has been investigated in vitro. Dilated hmMSCs were slightly bigger in size, grew slower, but had almost the same levels of MSC-typical surface markers as healthy hmMSCs. Histone deacetylase (HDAC) activity in dilated hmMSCs was 1.5-fold higher than in healthy ones, which was suppressed by class I and II HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) showing activation of cardiomyogenic differentiation-related genes alpha-cardiac actin (ACTC1) and cardiac troponin T (TNNT2). Both types of hmMSCs cultivated on collagen I hydrogels with hyaluronic acid (HA) or 2-methacryloyloxyethyl phosphorylcholine (MPC) and exposed to SAHA significantly downregulated focal adhesion kinase (PTK2) and activated ACTC1 and TNNT2. Longitudinal cultivation of dilated hmMSC also upregulated alpha-cardiac actin. Thus, HDAC inhibitor SAHA, in combination with collagen I-based hydrogels, can tilt the dilated myocardium hmMSC toward cardiomyogenic direction in vitro with further possible therapeutic application in vivo. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
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13 pages, 2598 KiB  
Article
SH3-Binding Glutamic Acid Rich-Deficiency Augments Apoptosis in Neonatal Rat Cardiomyocytes
by Anushka Deshpande, Ankush Borlepawar, Alexandra Rosskopf, Derk Frank, Norbert Frey and Ashraf Yusuf Rangrez
Int. J. Mol. Sci. 2021, 22(20), 11042; https://doi.org/10.3390/ijms222011042 - 13 Oct 2021
Cited by 4 | Viewed by 2065
Abstract
Congenital heart disease (CHD) is one of the most common birth defects in humans, present in around 40% of newborns with Down’s syndrome (DS). The SH3 domain-binding glutamic acid-rich (SH3BGR) gene, which maps to the DS region, belongs to a gene family encoding [...] Read more.
Congenital heart disease (CHD) is one of the most common birth defects in humans, present in around 40% of newborns with Down’s syndrome (DS). The SH3 domain-binding glutamic acid-rich (SH3BGR) gene, which maps to the DS region, belongs to a gene family encoding a cluster of small thioredoxin-like proteins sharing SH3 domains. Although its expression is confined to the cardiac and skeletal muscle, the physiological role of SH3BGR in the heart is poorly understood. Interestingly, we observed a significant upregulation of SH3BGR in failing hearts of mice and human patients with hypertrophic cardiomyopathy. Along these lines, the overexpression of SH3BGR exhibited a significant increase in the expression of hypertrophic markers (Nppa and Nppb) and increased cell surface area in neonatal rat ventricular cardiomyocytes (NRVCMs), whereas its knockdown attenuated cellular hypertrophy. Mechanistically, using serum response factor (SRF) response element-driven luciferase assays in the presence or the absence of RhoA or its inhibitor, we found that the pro-hypertrophic effects of SH3BGR are mediated via the RhoA–SRF axis. Furthermore, SH3BGR knockdown resulted in the induction of apoptosis and reduced cell viability in NRVCMs via apoptotic Hippo–YAP signaling. Taking these results together, we here show that SH3BGR is vital for maintaining cytoskeletal integrity and cellular viability in NRVCMs through its modulation of the SRF/YAP signaling pathways. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
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23 pages, 3606 KiB  
Article
Compromised Biomechanical Properties, Cell–Cell Adhesion and Nanotubes Communication in Cardiac Fibroblasts Carrying the Lamin A/C D192G Mutation
by Veronique Lachaize, Brisa Peña, Catalin Ciubotaru, Dan Cojoc, Suet Nee Chen, Matthew R. G. Taylor, Luisa Mestroni and Orfeo Sbaizero
Int. J. Mol. Sci. 2021, 22(17), 9193; https://doi.org/10.3390/ijms22179193 - 25 Aug 2021
Cited by 5 | Viewed by 2566
Abstract
Clinical effects induced by arrhythmogenic cardiomyopathy (ACM) originate from a large spectrum of genetic variations, including the missense mutation of the lamin A/C gene (LMNA), LMNA D192G. The aim of our study was to investigate the biophysical and biomechanical impact of [...] Read more.
Clinical effects induced by arrhythmogenic cardiomyopathy (ACM) originate from a large spectrum of genetic variations, including the missense mutation of the lamin A/C gene (LMNA), LMNA D192G. The aim of our study was to investigate the biophysical and biomechanical impact of the LMNA D192G mutation on neonatal rat ventricular fibroblasts (NRVF). The main findings in mutated NRVFs were: (i) cytoskeleton disorganization (actin and intermediate filaments); (ii) decreased elasticity of NRVFs; (iii) altered cell–cell adhesion properties, that highlighted a strong effect on cellular communication, in particular on tunneling nanotubes (TNTs). In mutant-expressing fibroblasts, these nanotubes were weakened with altered mechanical properties as shown by atomic force microscopy (AFM) and optical tweezers. These outcomes complement prior investigations on LMNA mutant cardiomyocytes and suggest that the LMNA D192G mutation impacts the biomechanical properties of both cardiomyocytes and cardiac fibroblasts. These observations could explain how this mutation influences cardiac biomechanical pathology and the severity of ACM in LMNA-cardiomyopathy. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
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14 pages, 3313 KiB  
Article
YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes
by Yunan Gao, Yan Sun, Adife Gulhan Ercan-Sencicek, Justin S. King, Brynn N. Akerberg, Qing Ma, Maria I. Kontaridis, William T. Pu and Zhiqiang Lin
Int. J. Mol. Sci. 2021, 22(13), 6649; https://doi.org/10.3390/ijms22136649 - 22 Jun 2021
Cited by 13 | Viewed by 3396
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
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21 pages, 6080 KiB  
Article
Implications of the Wilms’ Tumor Suppressor Wt1 in Cardiomyocyte Differentiation
by Nicole Wagner, Marina Ninkov, Ana Vukolic, Günseli Cubukcuoglu Deniz, Minoo Rassoulzadegan, Jean-François Michiels and Kay-Dietrich Wagner
Int. J. Mol. Sci. 2021, 22(9), 4346; https://doi.org/10.3390/ijms22094346 - 21 Apr 2021
Cited by 13 | Viewed by 3164
Abstract
The Wilms’ tumor suppressor Wt1 is involved in multiple developmental processes and adult tissue homeostasis. The first phenotypes recognized in Wt1 knockout mice were developmental cardiac and kidney defects. Wt1 expression in the heart has been described in epicardial, endothelial, smooth muscle cells, [...] Read more.
The Wilms’ tumor suppressor Wt1 is involved in multiple developmental processes and adult tissue homeostasis. The first phenotypes recognized in Wt1 knockout mice were developmental cardiac and kidney defects. Wt1 expression in the heart has been described in epicardial, endothelial, smooth muscle cells, and fibroblasts. Expression of Wt1 in cardiomyocytes has been suggested but remained a controversial issue, as well as the role of Wt1 in cardiomyocyte development and regeneration after injury. We determined cardiac Wt1 expression during embryonic development, in the adult, and after cardiac injury by quantitative RT-PCR and immunohistochemistry. As in vitro model, phenotypic cardiomyocyte differentiation, i.e., the appearance of rhythmically beating clones from mouse embryonic stem cells (mESCs) and associated changes in gene expression were analyzed. We detected Wt1 in cardiomyocytes from embryonic day (E10.5), the first time point investigated, until adult age. Cardiac Wt1 mRNA levels decreased during embryonic development. In the adult, Wt1 was reactivated in cardiomyocytes 48 h and 3 weeks following myocardial infarction. Wt1 mRNA levels were increased in differentiating mESCs. Overexpression of Wt1(-KTS) and Wt1(+KTS) isoforms in ES cells reduced the fraction of phenotypically cardiomyocyte differentiated clones, which was preceded by a temporary increase in c-kit expression in Wt1(-KTS) transfected ES cell clones and induction of some cardiomyocyte markers. Taken together, Wt1 shows a dynamic expression pattern during cardiomyocyte differentiation and overexpression in ES cells reduces their phenotypical cardiomyocyte differentiation. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
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Review

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21 pages, 1062 KiB  
Review
Recent Advances in Gene Therapy for Cardiac Tissue Regeneration
by Yevgeniy Kim, Zharylkasyn Zharkinbekov, Madina Sarsenova, Gaziza Yeltay and Arman Saparov
Int. J. Mol. Sci. 2021, 22(17), 9206; https://doi.org/10.3390/ijms22179206 - 26 Aug 2021
Cited by 10 | Viewed by 3621
Abstract
Cardiovascular diseases (CVDs) are responsible for enormous socio-economic impact and the highest mortality globally. The standard of care for CVDs, which includes medications and surgical interventions, in most cases, can delay but not prevent the progression of disease. Gene therapy has been considered [...] Read more.
Cardiovascular diseases (CVDs) are responsible for enormous socio-economic impact and the highest mortality globally. The standard of care for CVDs, which includes medications and surgical interventions, in most cases, can delay but not prevent the progression of disease. Gene therapy has been considered as a potential therapy to improve the outcomes of CVDs as it targets the molecular mechanisms implicated in heart failure. Cardiac reprogramming, therapeutic angiogenesis using growth factors, antioxidant, and anti-apoptotic therapies are the modalities of cardiac gene therapy that have led to promising results in preclinical studies. Despite the benefits observed in animal studies, the attempts to translate them to humans have been inconsistent so far. Low concentration of the gene product at the target site, incomplete understanding of the molecular pathways of the disease, selected gene delivery method, difference between animal models and humans among others are probable causes of the inconsistent results in clinics. In this review, we discuss the most recent applications of the aforementioned gene therapy strategies to improve cardiac tissue regeneration in preclinical and clinical studies as well as the challenges associated with them. In addition, we consider ongoing gene therapy clinical trials focused on cardiac regeneration in CVDs. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
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22 pages, 416 KiB  
Review
Every Beat You Take—The Wilms′ Tumor Suppressor WT1 and the Heart
by Nicole Wagner and Kay-Dietrich Wagner
Int. J. Mol. Sci. 2021, 22(14), 7675; https://doi.org/10.3390/ijms22147675 - 18 Jul 2021
Cited by 9 | Viewed by 3247
Abstract
Nearly three decades ago, the Wilms’ tumor suppressor Wt1 was identified as a crucial regulator of heart development. Wt1 is a zinc finger transcription factor with multiple biological functions, implicated in the development of several organ systems, among them cardiovascular structures. This review [...] Read more.
Nearly three decades ago, the Wilms’ tumor suppressor Wt1 was identified as a crucial regulator of heart development. Wt1 is a zinc finger transcription factor with multiple biological functions, implicated in the development of several organ systems, among them cardiovascular structures. This review summarizes the results from many research groups which allowed to establish a relevant function for Wt1 in cardiac development and disease. During development, Wt1 is involved in fundamental processes as the formation of the epicardium, epicardial epithelial-mesenchymal transition, coronary vessel development, valve formation, organization of the cardiac autonomous nervous system, and formation of the cardiac ventricles. Wt1 is further implicated in cardiac disease and repair in adult life. We summarize here the current knowledge about expression and function of Wt1 in heart development and disease and point out controversies to further stimulate additional research in the areas of cardiac development and pathophysiology. As re-activation of developmental programs is considered as paradigm for regeneration in response to injury, understanding of these processes and the molecules involved therein is essential for the development of therapeutic strategies, which we discuss on the example of WT1. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
29 pages, 1279 KiB  
Review
Engineering and Assessing Cardiac Tissue Complexity
by Karine Tadevosyan, Olalla Iglesias-García, Manuel M. Mazo, Felipe Prósper and Angel Raya
Int. J. Mol. Sci. 2021, 22(3), 1479; https://doi.org/10.3390/ijms22031479 - 02 Feb 2021
Cited by 11 | Viewed by 5340
Abstract
Cardiac tissue engineering is very much in a current focus of regenerative medicine research as it represents a promising strategy for cardiac disease modelling, cardiotoxicity testing and cardiovascular repair. Advances in this field over the last two decades have enabled the generation of [...] Read more.
Cardiac tissue engineering is very much in a current focus of regenerative medicine research as it represents a promising strategy for cardiac disease modelling, cardiotoxicity testing and cardiovascular repair. Advances in this field over the last two decades have enabled the generation of human engineered cardiac tissue constructs with progressively increased functional capabilities. However, reproducing tissue-like properties is still a pending issue, as constructs generated to date remain immature relative to native adult heart. Moreover, there is a high degree of heterogeneity in the methodologies used to assess the functionality and cardiac maturation state of engineered cardiac tissue constructs, which further complicates the comparison of constructs generated in different ways. Here, we present an overview of the general approaches developed to generate functional cardiac tissues, discussing the different cell sources, biomaterials, and types of engineering strategies utilized to date. Moreover, we discuss the main functional assays used to evaluate the cardiac maturation state of the constructs, both at the cellular and the tissue levels. We trust that researchers interested in developing engineered cardiac tissue constructs will find the information reviewed here useful. Furthermore, we believe that providing a unified framework for comparison will further the development of human engineered cardiac tissue constructs displaying the specific properties best suited for each particular application. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
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13 pages, 1983 KiB  
Brief Report
Bmp Signaling Regulates Hand1 in a Dose-Dependent Manner during Heart Development
by Mingjie Zheng, Shannon Erhardt, Di Ai and Jun Wang
Int. J. Mol. Sci. 2021, 22(18), 9835; https://doi.org/10.3390/ijms22189835 - 11 Sep 2021
Cited by 4 | Viewed by 2488
Abstract
The bone morphogenetic protein (Bmp) signaling pathway and the basic helix–loop–helix (bHLH) transcription factor Hand1 are known key regulators of cardiac development. In this study, we investigated the Bmp signaling regulation of Hand1 during cardiac outflow tract (OFT) development. In Bmp2 and Bmp4 [...] Read more.
The bone morphogenetic protein (Bmp) signaling pathway and the basic helix–loop–helix (bHLH) transcription factor Hand1 are known key regulators of cardiac development. In this study, we investigated the Bmp signaling regulation of Hand1 during cardiac outflow tract (OFT) development. In Bmp2 and Bmp4loss-of-function embryos with varying levels of Bmp in the heart, Hand1 is sensitively decreased in response to the dose of Bmp expression. In contrast, Hand1 in the heart is dramatically increased in Bmp4 gain-of-function embryos. We further identified and characterized the Bmp/Smad regulatory elements in Hand1. Combined transfection assays and chromatin immunoprecipitation (ChIP) experiments indicated that Hand1 is directly activated and bound by Smads. In addition, we found that upon the treatment of Bmp2 and Bmp4, P19 cells induced Hand1 expression and favored cardiac differentiation. Together, our data indicated that the Bmp signaling pathway directly regulates Hand1 expression in a dose-dependent manner during heart development. Full article
(This article belongs to the Special Issue Transcriptional Regulation of Cardiac Development and Disease)
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