scholarly journals Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects

2021 ◽  
Vol 8 (3) ◽  
pp. 29
Author(s):  
Carmen Leung ◽  
Anish Engineer ◽  
Mella Y. Kim ◽  
Xiangru Lu ◽  
Qingping Feng
Keyword(s):  
Heart Development ◽  
Planar Cell Polarity ◽  
Cardiac Development ◽  
Current Knowledge ◽  
Ventricular Myocardium ◽  
Double Outlet Right Ventricle ◽  
Left Ventricular ◽  
Small Gtpase ◽  
Ventricular Noncompaction ◽  
Specific Deletion

Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTPase Rac1 acts as a crucial regulator of numerous developmental events. The present study aimed to investigate the cardiomyocyte specific role of Rac1 in embryonic heart development. Methods and Results: The Nkx2.5-Cre transgenic mice were crossed with Rac1f/f mice to generate mice with a cardiomyocyte specific deletion of Rac1 (Rac1Nkx2.5) during heart development. Embryonic Rac1Nkx2.5 hearts at E12.5–E18.5 were collected for histological analysis. Overall, Rac1Nkx2.5 hearts displayed a bifid apex, along with hypertrabeculation and a thin compact myocardium. Rac1Nkx2.5 hearts also exhibited ventricular septal defects (VSDs) and double outlet right ventricle (DORV) or overriding aorta. Cardiomyocytes had a rounded morphology and were highly disorganized, and the myocardial expression of Scrib, a planar cell polarity protein, was reduced in Rac1Nkx2.5 hearts. In addition, cell proliferation rate was significantly decreased in the Rac1Nkx2.5 ventricular myocardium at E9.5. Conclusions: Rac1 deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in Rac1Nkx2.5 hearts, implicating Rac1 signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development.

Abstract MP174: Cardiomyocyte-specific Deletion of Parathyroid Hormone Receptor 1 During Development Leads to Left Ventricular Hypoplasia

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Desiree Leach ◽  
Ryan Jorgensen ◽  
Jayne Wolfe ◽  
Lisa D Wilsbacher
Keyword(s):  
Parathyroid Hormone ◽  
Heart Development ◽  
Hormone Receptor ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Camp Production ◽  
Parathyroid Hormone Receptor ◽  
Specific Deletion

Congenital heart defects occur in approximately 1% of all births and signify the most common human birth defects. Our lab previously demonstrated that cardiomyocyte specific deletion of Sphingosine 1-Phosphate Receptor 1 (S1P 1 ), a G protein-coupled receptor (GPCR) that couples exclusively to Gαi, leads to ventricular noncompaction in mice. Gαs- and Gαi-coupled GPCRs activate and inhibit adenylate cyclase, respectively, thereby regulating cAMP production. These GPCRs play important roles in adult cardiac health and disease, but their contributions to heart development are not well understood. We hypothesized that tight regulation of cAMP via Gαs- and Gαi-coupled GPCRs is a critical determinant of cardiomyocyte maturation and cardiac development. Here, we report that Parathyroid Hormone Receptor 1 (Pth1r) which couples to Gαs, is a mediator of cardiomyocyte maturation. Using mice with a Cre allele in the myosin light chain 2a locus ( Myl7 Cre/+, also known as Mlc2a Cre/+ ), we found that cardiomyocyte-specific deletion of Pth1r during development led to reduced postnatal survival. Hearts collected from surviving Pth1r cardiomyocyte mutant mice displayed left ventricular (LV) hypoplasia, and fetal cardiac genes Nppa (natriuretic peptide A) and β myosin heavy chain (Myh7) were upregulated in the hearts of surviving mutants. At 14.5 days post coitus (dpc) and 18.5 dpc, Pth1r cardiomyocyte mutant mice also showed LV hypoplasia. Furthermore, we observed decreased cardiomyocyte proliferation in Pth1r cardiomyocyte mutant hearts during development. Isolated cardiomyocytes from C57BL/6 wild-type embryos showed increased cAMP production after stimulation of Pth1r; Pth1r-dependent cAMP increases were inhibited by activation of S1P 1 . Overall, our results indicate a critical role for Pth1r signaling during heart development and suggest that cAMP levels must be tightly controlled in cardiomyocytes for normal cardiac development. LV hypoplasia is one of the key features of hypoplastic left heart syndrome (HLHS), one of the most severe forms of congenital heart disease; these studies may provide new approaches for the study and treatment of LV hypoplasia and HLHS.

scholarly journals Heart transplantation in an adult patient with isolated noncompaction of the left ventricular myocardium

Medicina ◽  
2010 ◽  
Vol 46 (3) ◽  
pp. 193 ◽  
Author(s):  
Sigita Glaveckaitė ◽  
Kęstutis Ručinskas ◽  
Jelena Čelutkienė ◽  
Vytė Maneikienė ◽  
Diana Zakarkaitė ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Adult Patient ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Important Process ◽  
Ventricular Noncompaction ◽  
Myocardial Development ◽  
Myocardial Fibers ◽  
Heart Lesions

Isolated noncompaction of the ventricular myocardium is defined as a rare cardiomyopathy caused by intrauterine arrest of compaction of the myocardial fibers and meshwork, an important process in myocardial development, in absence of any coexisting congenital heart lesions. A lot of controversies exist about diagnostic criteria, nomenclature, origin, pathogenesis, and prognosis of this disease. Here, we describe an adult patient with isolated left ventricular noncompaction who presented with worsening congestive heart failure and was successfully treated with heart transplantation.

scholarly journals DIAGNOSTIC OF THE ATHLETE’S HEART AND FACTORS AFFECTING ITS DEVELOPING

2021 ◽  
Vol 74 (5) ◽  
pp. 1158-1163
Author(s):  
Serhiy V. Popov ◽  
Oleksandr I. Smiyan ◽  
Andrii M. Loboda ◽  
Viktoriia O. Petrashenko ◽  
Olena K. Redko ◽  
...  
Keyword(s):  
Left Ventricle ◽  
Heart Development ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Athlete’S Heart ◽  
Left Ventricular Myocardium ◽  
Factors Affecting ◽  
Ultrasound Study ◽  
And Function ◽  
Athlete's Heart

The aim: Studying the features of the structure and function of the heart in athletes and identifying the factors that influence the development of these changes. Materials and methods: The study included 54 athletes, 29 men and 25 women. The ultrasound study was performed according to standard methods with determining the size of the main structures of the heart, indicators normalized to body surface area, height. Results: The heart of dilatation and hypertrophy of the left ventricular myocardium were found in 25.93% of the athletes. When comparing the diameter of the left ventricle of individual athletes with the average values of the norm, their excess was found in 94.44% of athletes. The Odds ratio (OR) of the relationship between left ventricle diameter (LVd) and time of the exercise less than 10 y was 16.13, time of the exercise less than 5 y – 0.17 (p <0.05). OR of increase LVd to age less than 20 years was 3.56 units (p <0.05). The ejection fraction was above the normative mean in 75.93%, as well as the ratio of the periods of filling of the ventricles. Conclusions: The most common sign of an athlete’s heart development was left ventricular dilatation, which occurred at a rate of 25 percent. Age less than 20 years and the duration of sports activities from 5 to 10 years is associated with a higher frequency of the athlete’s heart.

scholarly journals An alternatively spliced zebrafish jnk1a transcript has an essential and non-redundant role in development of the first heart field derived proximal ventricular chamber

2019 ◽  
Author(s):  
A Santos-Ledo ◽  
S Washer ◽  
T Dhanaseelan ◽  
P Chrystal ◽  
T Papoutsi ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Heart Development ◽  
Planar Cell Polarity ◽  
Cardiac Development ◽  
Single Gene ◽  
Jun Kinase ◽  
Downstream Effectors ◽  
Heart Malformation ◽  
Alternatively Spliced ◽  
First Heart Field

AbstractAlternative splicing is a ubiquitous mechanism for producing different mRNA species from a single gene, resulting in proteomic diversity. Despite potential for regulating embryogenesis, its developmental role remains under-investigated. The Jun kinase (Jnk) genes, considered downstream effectors of the non-canonical Wnt planar cell polarity pathway, utilise extensive and evolutionarily-conserved alternative splicing. Although many PCP members are associated with heart malformation, the role of Jnk genes in cardiac development, and specifically which alternatively spliced transcripts orchestrate these processes, remain unknown. In this study we exploit the jnk1 duplication and subspecialisation found in zebrafish to reveal an essential and non-redundant requirement for jnk1a in cardiac development. We characterise alternatively spliced jnk1a/jnk1b transcripts and demonstrate that hypoplasia of the proximal ventricular component, which corresponds to human hypoplastic left ventricle, can only be rescued by the jnk1a Ex7 Lg transcript. These studies highlight the importance of Jnk signalling and alternative splicing in heart development

Abstract 132: The First Mouse Mutants of a Novel Epigenetic Modifier, Rearranged L-Myc Fusion, Display Defects in Heart Development

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Lauren M Bourke ◽  
Sarah Harten ◽  
Vandhana Bharti ◽  
Harry Oey ◽  
Nadia Whitelaw ◽  
...  
Keyword(s):  
Heart Development ◽  
Critical Role ◽  
Interventricular Septum ◽  
Notch Pathway ◽  
Regulatory Elements ◽  
Left Ventricular ◽  
Wild Type ◽  
Ventricular Noncompaction ◽  
Mouse Mutants ◽  
Epigenetic Modifier

Rearranged L-Myc Fusion, Rlf, was recently identified as a novel epigenetic modifier from a mouse N-ethyl-N-nitrosourea mutagenesis screen. The mice used in this study carry a multi-copy green fluorescent protein (GFP) transgene linked to an erythroid specific α-globin promoter that is sensitive to epigenetic silencing. Three independent mouse lines with mutations in Rlf were each found to have a decrease in GFP expression, suggesting Rlf acts an epigenetic modifier. Our study is the first to reveal a role for Rlf in epigenetics. Preliminary phenotyping has found loss of Rlf results in perinatal lethality. Late gestation homozygous null Rlf mutants were found to weigh significantly less than their heterozygous or wild type littermates. Histological analysis of mid gestation embryos has identified a potential heart defect in homozygous mutants. Rlf mutants display a thin compact layer, an overabundance of trabeculae and a fenestrated interventricular septum. The Rlf mutant phenotype is reminiscent of ventricular noncompaction defects observed in humans, such as left ventricular noncompaction cardiomyopathy. RNA-seq analysis of mid gestation Rlf wild type and null hearts, prior to the observation of a cardiac defect, was undertaken to determine which pathways may be regulated by Rlf in the heart. More genes were observed to be significantly down-regulated in Rlf mutant hearts compared to wild types. Pathway analysis of differentially expressed genes showed genes involved in cell-cell adhesion, cell signalling, glycosylation and the Notch pathway were dysregulated. These findings indicate that Rlf may play a critical role in cardiac development. Whole genome bisulphite sequencing of different embryonic tissue/stages has shown loss of Rlf results in an increase in methylation at a large number of distinct loci across the genome. Many of which were found to overlap sites reported to be putative regulatory elements, and histone marks associated with active or poised regulatory elements in the heart. Our data suggest Rlf plays a key role in regulating gene expression pathways during heart development. These are the first mouse mutants available to study how Rlf functions as an epigenetic modifier and the phenotypic consequences of Rlf inactivation.

scholarly journals Neddylation mediates ventricular chamber maturation through repression of Hippo signaling

2018 ◽  
Vol 115 (17) ◽  
pp. E4101-E4110 ◽  
Author(s):  
Jianqiu Zou ◽  
Wenxia Ma ◽  
Jie Li ◽  
Rodney Littlejohn ◽  
Hongyi Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Development ◽  
Molecular Mechanisms ◽  
Heart Defects ◽  
Left Ventricular ◽  
Late Gestation ◽  
Hippo Signaling ◽  
Cardiomyocyte Proliferation ◽  
Ventricular Noncompaction ◽  
Cullin 7

During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling.

scholarly journals Isolated Left Ventricular Noncompaction Cardiomyopathy Diagnosed by Transesophageal Echocardiography

2011 ◽  
Vol 5 ◽  
pp. CMC.S6240 ◽  
Author(s):  
Tariq Bhat ◽  
James Lafferty ◽  
Sumaya Teli ◽  
Georges Abou Rjaili ◽  
Yefim Olkovsky ◽  
...  
Keyword(s):  
Transesophageal Echocardiography ◽  
Case Reports ◽  
Case Series ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Noncompaction ◽  
Ventricular Noncompaction ◽  
Noncompaction Cardiomyopathy ◽  
Left Ventricular Noncompaction Cardiomyopathy

Isolated noncompaction of the ventricular myocardium has often been misdiagnosed as other cardiomyopathies because it is a relatively recently described cardiomyopathy with literature limited to case reports and case series and little awareness among physicians. We are reporting a case of isolated left ventricular noncompaction cardiomyopathy that was misdiagnosed for over two decades.

The molecular basis of cardiac embryogenesis

ESC CardioMed ◽  
2018 ◽  
pp. 36-39
Author(s):  
Miguel Torres
Keyword(s):  
Heart Development ◽  
Molecular Basis ◽  
Cardiac Development ◽  
Current Knowledge ◽  
Cell Lineage ◽  
Postnatal Period ◽  
Circulatory Support ◽  
Lineage Specification ◽  
Mammalian Embryo ◽  
Chromatin Regulators

The heart is the first organ to function in the mammalian embryo; however, heart development spans the whole intrauterine period and is only completed during the postnatal period. The ability of the mammalian fetal heart to provide circulatory support while preserving its proliferative and regenerative ability has stimulated interest in the molecular and cellular pathways underlying cardiac development and how they might be exploited in the design of regenerative strategies in the adult heart. Cardiac cell lineage specification and differentiation is regulated by an intricate network of molecular pathways that involve extracellular signals, transcription factors, and chromatin regulators. This chapter outlines current knowledge and the latest advances in understanding the molecular basis of cardiac lineage specification and differentiation during embryonic development.

scholarly journals Every Beat You Take—The Wilms′ Tumor Suppressor WT1 and the Heart

2021 ◽  
Vol 22 (14) ◽  
pp. 7675
Author(s):  
Nicole Wagner ◽  
Kay-Dietrich Wagner
Keyword(s):  
Tumor Suppressor ◽  
Heart Development ◽  
Epithelial Mesenchymal Transition ◽  
Cardiac Development ◽  
Wilms Tumor ◽  
Current Knowledge ◽  
Adult Life ◽  
Autonomous Nervous System ◽  
Mesenchymal Transition ◽  
Organ Systems

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.

scholarly journals Myocardial Notch-Rbpj deletion does not affect heart development or function

2018 ◽  
Author(s):  
Alejandro Salguero-Jiménez ◽  
Joaquim Grego-Bessa ◽  
Gaetano D’Amato ◽  
Luis J. Jiménez-Borreguero ◽  
José Luis de la Pompa
Keyword(s):  
Notch Signaling ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Function ◽  
Physiological Role ◽  
Double Outlet Right Ventricle ◽  
Cardiac Valves ◽  
Myocardial Development ◽  
Normal Expression ◽  
And Function

AbstractDuring vertebrate cardiac development NOTCH signaling activity in the endocardium is essential for the crosstalk between endocardium and myocardium that initiates ventricular trabeculation and valve primordium formation. This crosstalk leads later to the maturation and compaction of the ventricular chambers and the morphogenesis of the cardiac valves, and its alteration may lead to disease. Although endocardial NOTCH signaling has been shown to be crucial for heart development, its physiological role in the myocardium has not been clearly established. Here we have used a genetic strategy to evaluate the role of NOTCH in myocardial development. We have inactivated the unique and ubiquitous NOTCH effector RBPJ in the early cardiomyocytes progenitors, and examined its consequences in cardiac development and function. Our results demonstrate that mice with cTnT-Cre-mediated myocardial-specific deletion of Rbpj develop to term, with homozygous mutant animals showing normal expression of cardiac development markers, and normal adult heart function. Similar observations have been obtained after Notch1 deletion with cTnT-Cre. We have also deleted Rbpj in both myocardial and endocardial progenitor cells, using the Nkx2.5-Cre driver, resulting in ventricular septal defect (VSD), double outlet right ventricle (DORV), and bicuspid aortic valve (BAV), due to NOTCH signaling abrogation in the endocardium of cardiac valves territories. Our data demonstrate that NOTCH-RBPJ inactivation in the myocardium does not affect heart development or adult cardiac function.

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