Partial loss of GATA factor Pannier impairs adult heart function in Drosophila

Ulcerative colitis and Crohn’s disease are classified as chronic inflammatory bowel diseases (IBD) with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. Our objective was to identify microRNAs mediating molecular remodeling and resulting cardiac impairment in a rat model of colitis. To induce chronic colitis, dextran sodium sulfate (DSS) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Echocardiography was performed to evaluate heart function. DSS-induced colitis led to a significant decrease in ejection fraction, increased left ventricular mass and size, and elevated B-type natriuretic protein. MicroRNA profiling showed a total of 56 miRNAs significantly increased in the heart by colitis, 8 of which are predicted to target brain-derived neurotrophic factor (BDNF). RT-qPCR validated the increases of miR-1b, Let-7d, and miR-155. Transient transfection revealed that miR-155 significantly suppresses BDNF in H9c2 cells. Importantly, DSS colitis markedly decreased BDNF in both myocardium and serum. Levels of various proteins critical to cardiac homeostasis were also altered. Functional studies showed that BDNF increases cell viability and mitigates H2O2-induced oxidative damage in H9c2 cells, demonstrating its protective role in the adult heart. Mechanistically, cellular experiments identified IL-1β as the inflammatory mediator upregulating cardiac miR-155; this effect was confirmed in adult rats. Furthermore, IL-1β neutralizing antibody ameliorated the DSS-induced increase in miR-155 and concurrent decrease in BDNF in the adult heart, showing therapeutic potential. Our findings indicate that chronic colitis impairs heart function through an IL-1β→miR-155→BDNF signaling axis.

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Abstract 519: Talin is Required for Normal Adult Heart Function

Circulation Research ◽

10.1161/res.127.suppl_1.519 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Yoshitake Cho ◽

Ruixia Li ◽

Ana M Manso ◽

Robert S Ross

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Cardiac Development ◽

Heart Function ◽

Left Ventricular ◽

Mass Spectrometry Analysis ◽

Adult Heart ◽

Spectrometry Analysis ◽

Functional Changes

Talin (Tln) is a component of muscle costameres that links integrins to other components of the cellular cytoskeleton and plays an important role in maintaining the cellular integrity of cardiac myocytes (CM). There are two talin genes, Tln1 and Tln2, expressed in the heart. Tln1 is ubiquitously expressed, and Tln2 is dominantly expressed in CM. In our previous study, we show that the global deletion of Tln2 in mice (T2KO) caused no structural or functional changes in the heart, presumably because CM Tln1 became up-regulated. However, we found that mice lacking both CM Tln1 and Tln2 exhibit cardiac dysfunction by 4 weeks (w) of age with 100% mortality by 6 months (m), showing Tln plays an essential role in cardiac development and in maintaining cardiac function. In this study, we produced a tamoxifen (Tamo)-inducible mouse model in which Tln1 could be explicitly reduced in the adult CM (T1icKO), and then generate T1icKO:T2KO (T1/2dKO), so that the function of Tln could be assessed in the postnatal heart. T2KO and Tln1/2dKO mice were injected with Tamo at 8w. Echocardiograms were performed to evaluate cardiac function up to 8w post-Tamo injection. While T2KO mice showed normal cardiac function, T1/2dKO exhibited a gradual decrease in function post-Tamo injection. At 8w post-Tamo injection, T1/2dKO mice showed cardiac hypertrophy, fibrosis, and heart failure. To understand the mechanism by which deletion CM talin leads to cardiac dysfunction, left ventricular tissue protein lysates from T2KO and T1/2dKO mice at 4w post-Tamo when cardiac function (echo) and structure were preserved in dKO. The protein lysates were subjected to quantitative mass spectrometry analysis. We found there are 1,100 proteins differentially expressed in T2KO and T1/2dKO hearts. Pathway analysis was performed, and the results showed that proteins involved in vesicle transport, protein folding, and innate immunity are most up-regulated in the T1/2dKO heart. Taken together, our results show that Tln is required for maintaining proper cardiac function in the adult heart. The deletion of Tln in CM results in the up-regulation of multiple intracellular pathways, and we are currently studying the role of each pathway in the pathogenesis of heart failure induced by CM Tln deletion.

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Neural Crest Derived Cardiomyocytes Regulate Cardiac Trabeculation and Adult Heart Function.

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.18.3 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Sarah Abdul‐Wajid ◽

Bradley Demarest ◽

H Joseph Yost

Keyword(s):

Neural Crest ◽

Heart Function ◽

Adult Heart

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Loss of embryonic neural crest cardiomyocytes causes adult hypertrophic cardiomyopathy

10.1101/270652 ◽

2018 ◽

Author(s):

Sarah Abdul-Wajid ◽

Bradley L Demarest ◽

H Joseph Yost

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Neural Crest ◽

Heart Function ◽

Adult Onset ◽

Adult Fish ◽

Stress Tests ◽

Zebrafish Model ◽

Adult Heart ◽

Cardiac Stress ◽

Developmental Mechanism

AbstractNeural crest cells migrate to the embryonic heart and transform into a small number of cardiomyocytes, but their functions in the developing and adult heart are unknown. Here, we map the fates of neural crest derived cardiomyocytes (NC-Cms) and genetically ablate them in embryogenesis in zebrafish. Specific NC-Cm ablation results in aberrant trabeculation patterns and altered Notch signaling, but is not detrimental to the development of the fish or early heart function. Strikingly, embryonic NC-Cm ablation results in adult fish that show severely hypertrabeculated hearts, altered cardiomyocyte size, diminished adult heart capacity and consequently poor physiological response to cardiac stress tests. Thus, we identify a novel developmental mechanism and genetic pathway that predisposes adults to hypertrophic cardiomyopathy and provides the first zebrafish model of adult-onset heart failure.

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α-E-Catenin is a potential regulator of canonical Wnt and HIPPO-signallings in myocardium

Visnik ukrains'kogo tovaristva genetikiv i selekcioneriv ◽

10.7124/visnyk.utgis.14.2.682 ◽

2016 ◽

Vol 14 (2) ◽

pp. 168-173 ◽

Cited By ~ 1

Author(s):

V. V. Balatskyy ◽

O. L. Palchevska ◽

L. L. Macewicz ◽

O. O. Piven

Keyword(s):

Structural Integrity ◽

Heart Function ◽

Homozygous Deletion ◽

Wnt Signalling ◽

Conditional Knockout ◽

Regulatory Function ◽

Adult Heart ◽

Genes Expression ◽

Canonical Wnt ◽

Hippo Signalling

The structural integrity of the myocardium is necessary for heart function and maintains by intercalated disks. Alpha-E-catenin – is important component of adherens junction in adult myocardium. In addition, during last time the possible signalling function of a-E-catenin was described. The aim of our work was to investigate the α-E-catenin regulatory function in canonical Wnt and HIPPO signalling in adult heart. Materials and methods. Our work was done with α- E-catenin conditional knockout mice and aMHC-Cre - transgenic animals using. Expression of genes involved in the canonical Wnt- and HIPPO signalling were analysed with rtPCR using. Canonical Wnt signalling activity was investigated by Western blot analysis. Result. We have shown that both heterozygous and homozygous deletion of α-E-catenin gene in the embryonic heart leads to activation of WNT / β-catenin signalling, namely we registered the higher level of c-Fos, c-Myc and Ctnnb1 genes expression and increasing of phosphorylated GSK3β in adult heart. In addition, we observed the HIPPO-signalling pathway activation after α- E-catenin gene ablation, namely we observed increasing of Ctgf, Il1rl1, Tnfrsf1b, Aurka genes expression. Conclusions. Α-E-catenin has an important signalling function in adult heart, namely α-E-catenin regulates cytoplasmic level of main transcriptional activators of the canonical Wnt- and HIPPO - signalling cascades: β-catenin and Yap what leas to limiting their signalling activity. Keywords: α-E-catenin, β-catenin, HIPPO, Wnt-signalling, gene expression, myocardium

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Next generation of heart regenerative therapies: progress and promise of cardiac tissue engineering

npj Regenerative Medicine ◽

10.1038/s41536-021-00140-4 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Miguel F. Tenreiro ◽

Ana F. Louro ◽

Paula M. Alves ◽

Margarida Serra

Keyword(s):

Tissue Engineering ◽

Stem Cell ◽

Cell Biology ◽

Cardiac Tissue ◽

Disease Modeling ◽

Heart Function ◽

Cardiac Tissues ◽

Adult Heart ◽

Improve Heart Function ◽

Regenerative Therapies

AbstractThe adult heart is a vital and highly specialized organ of the human body, with limited capability of self-repair and regeneration in case of injury or disease. Engineering biomimetic cardiac tissue to regenerate the heart has been an ambition in the field of tissue engineering, tracing back to the 1990s. Increased understanding of human stem cell biology and advances in process engineering have provided an unlimited source of cells, particularly cardiomyocytes, for the development of functional cardiac muscle, even though pluripotent stem cell-derived cardiomyocytes poorly resemble those of the adult heart. This review outlines key biology-inspired strategies reported to improve cardiomyocyte maturation features and current biofabrication approaches developed to engineer clinically relevant cardiac tissues. It also highlights the potential use of this technology in drug discovery science and disease modeling as well as the current efforts to translate it into effective therapies that improve heart function and promote regeneration.

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Molecular and Microscopic Analysis of Altered Gene Expression in Transgenic and Gene Targeted Mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100162521 ◽

1996 ◽

Vol 54 ◽

pp. 12-13

Author(s):

W. K. Jones ◽

J. Robbins

Keyword(s):

Gene Expression ◽

Pulmonary Veins ◽

Microscopic Analysis ◽

Mouse Tissue ◽

Adult Heart ◽

Heavy Chains ◽

Altered Gene Expression ◽

Altered Gene ◽

Pulmonary Myocardium

Two myosin heavy chains (MyHC) are expressed in the mammalian heart and are differentially regulated during development. In the mouse, the α-MyHC is expressed constitutively in the atrium. At birth, the β-MyHC is downregulated and replaced by the α-MyHC, which is the sole cardiac MyHC isoform in the adult heart. We have employed transgenic and gene-targeting methodologies to study the regulation of cardiac MyHC gene expression and the functional and developmental consequences of altered α-MyHC expression in the mouse.We previously characterized an α-MyHC promoter capable of driving tissue-specific and developmentally correct expression of a CAT (chloramphenicol acetyltransferase) marker in the mouse. Tissue surveys detected a small amount of CAT activity in the lung (Fig. 1a). The results of in situ hybridization analyses indicated that the pattern of CAT transcript in the adult heart (Fig. 1b, top panel) is the same as that of α-MyHC (Fig. 1b, lower panel). The α-MyHC gene is expressed in a layer of cardiac muscle (pulmonary myocardium) associated with the pulmonary veins (Fig. 1c). These studies extend our understanding of α-MyHC expression and delimit a third cardiac compartment.

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