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Cardiac Stretch-Induced Transcriptomic Changes are Axis-Dependent

ABSTRACT: The goal of this study was to examine the effect of the major axis of biaxial mechanical stretch on cardiac myocyte gene expression and to identify the signaling pathways and transcription factors regulating these changes. Neonatal cardiac myocytes were cultured on a micropatterned substrate, and the primary stretch axis was applied either parallel or transverse to the myofibril direction. RNA sequencing was conducted to study whole genomic expression changes after acute cardiac myocyte stretch. The results showed a more robust gene response to longitudinal than to transverse stretch. After 30 minutes of stretch, 53 and 168 genes were considered differentially expressed (DE) from transverse and longitudinal stretch, respectively. After 4 hours, the number of DE genes increased to 795 in longitudinal stretch while it decreased to 35 in transverse stretch. Gene ontology term (GO) analysis indicated enrichment of TF activity and protein kinase activity by both stretch axes; whereas longitudinal but not transverse stretch caused expression of genes involved in sarcomere organization and cytoskeletal protein binding.

ORGANISM(S): Mus musculus

PROVIDER: GSE83655 | GEO | 2019/06/01

REPOSITORIES: GEO

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Expression data from cyclically stretched engineered neonatal rat ventricuar myocyte (NRVM) tissues

Project description:Mechanical overload in the heart induces pathological remodeling that typcially leads to heart failure. We sought to build an in vitro model of heart failure by applying cyclic stretch to engineered isotropic (iso) and anisotropic (aniso) NRVM tissues. We used micoarrays to determine the effects of longitudinal and transvserse cyclic stretch on gene expression in engineered NRVM cardiac tissues. We found that cyclic stretch induced up-regulation of several known indicators of heart faliure, independent of the direction of stretch. NRVMs were seeded on silicone membranes coated with isotropic (iso) fibronectin (FN) or micropatterned with FN (aniso), cultured statically for 1h (t=0h), and stretched for increasing amount of time (t=6h, 24h, 96h) before RNA extraction and hybridization on Affymetrix microarrays. For aniso tissues, stretch was applied in either the longitudinal (long) or transverse (trans) direction. RNA was collected over six primary NRVM harvests and thus RNA was also extracted and analyzed from samples seeded for 1h (at t=0h) on iso FN to be used to normalize across cell harvests.

2013-01-30 | E-GEOD-43846 | biostudies-arrayexpress

Expression data from cyclically stretched engineered neonatal rat ventricuar myocyte (NRVM) tissues

2013-01-30 | GSE43846 | GEO

Mus musculus

Project description:Cardiac Stretch-Induced Transcriptomic Changes are Axis-Dependent

| PRJNA326600 | ENA

Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration.

Project description:Rationale: Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level. Objective: The objectives of our study were to determine if myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process. Methods and Results: We derived a core transcriptional signature of injury-induced cardiac myocyte regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo cardiac myocyte differentiation, in vitro cardiac myocyte explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of cardiac myocyte differentiation processes including reactivation of latent developmental programs similar to those observed during de-stabilization of a mature cardiac myocyte phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13 (IL13), which induced cardiac myocyte cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of IL13 signaling in cardiac myocytes. These downstream signaling molecules are also modulated in the regenerating mouse heart. Conclusions: Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration. Comparison of transcriptional programs of primary myocardial tissues sampled from neonatal mice and murine hearts undergoing post-injury regeneration, along with in vitro ESC-differentiated cardiomyocytes

2014-12-20 | E-GEOD-64403 | biostudies-arrayexpress

Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration.

2014-12-20 | GSE64403 | GEO

Transcriptome analysis of zebrafish heart exposed to sorafenib

Project description:Sorafenib is associated with cardiac adverse effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish. A pigmentless zebrafish line expressing green fluorescent protein in the heart were treated with or without sorafenib. In vivo fluorescent cardiac imaging revealed that the ventricular dimension of the longitudinal axis in zebrafish treated with sorafenib was significantly lower than in those without sorafenib. Transcriptome analysis of zebrafish hearts revealed that expression of stanniocalcin1 (stc1) in zebrafish treated with sorafenib was significantly lower than that without sorafenib treatment. We were able to demonstrate that the ventricular dimension of the longitudinal axis in stc1 morphant was significantly smaller than that of control zebrafish and that forced expression of stc1 normalized the decrease in ventricular diameter in stc1 morphant and zebrafish treated with sorafenib. These data suggest that stc1 is the gene responsible for sorafenib-induced cardiotoxicity. Gene expression regulated by sorafenib in zebrafish at 4 dpf was measured. Four independent experiments were performed for each group.

2014-12-04 | E-GEOD-61155 | biostudies-arrayexpress

CHD4 and the NuRD complex directly control cardiac sarcomere formation

Project description:Cardiac development relies on proper cardiomyocyte differentiation including expression and assembly of cell-type specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of non-cardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and system genome-wide analyses of CHD4 localization, we identified novel CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development.

2018-05-15 | GSE109012 | GEO

Rattus norvegicus

Project description:Fibronectin Induced Cardiac Myocyte Hypertrophy

| PRJNA87131 | ENA

Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure

Project description:Heart failure is the major cause of death for muscular dystrophy patients; however, the molecular pathomechanism remains unknown. Here, we show the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced alpha-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and thus, the results may lead to strategies for therapeutic intervention.

2019-11-08 | GSE138280 | GEO

Wnt5a-YAP signaling axis mediates mechanotransduction in cardiac myocytes and contributes to the transition to heart failure (rat sample)

Project description:Non-canonical Wnt signaling activated by Wnt5a and Wnt11 is required for the development of second heart field cardiac progenitor cells in mice. However, the pathophysiological role of non-canonical Wnt signaling in the adult heart has not been fully elucidated. Here we show that cardiomyocyte-specific Wnt5a knockout mice exhibit improved systolic function and reduced expression of mechanosensitive genes including Nppb compared to control mice when subjected to pressure overload. In cultured cardiac myocytes, Wnt5a knockdown reduces the upregulation of Nppb gene expression and YAP nuclear translocation induced by cyclic cell stretch. Wnt5a knockdown-induced Nppb downregulation in response to cell stretch is rescued by inhibition of Hippo pathway, and the rescue effect of Hippo inhibition is canceled by YAP knockdown. These results collectively suggest that Wnt5a-YAP signaling axis mediates mechanotransduction in cardiac myocytes and contributes to the transition to heart failure.

2023-07-17 | GSE200666 | GEO

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