Ontology highlight
ABSTRACT:
PROVIDER: PRJNA939393 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23636849.fastq.gz | Fastqsanger.gz | |||
| SRR23636850.fastq.gz | Fastqsanger.gz | |||
| SRR23636851.fastq.gz | Fastqsanger.gz | |||
| SRR23636852.fastq.gz | Fastqsanger.gz | |||
| SRR23636853.fastq.gz | Fastqsanger.gz |
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Project description:Aim - Pathological cardiac remodeling is characterized by cardiomyocyte hypertrophy and fibroblast activation, which can ultimately lead to heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here we aimed for a more detailed view on molecular changes driving cardiomyocyte hypertrophy and failure to aid in the development of therapies to reverse maladaptive remodeling. Methods and results - Utilizing cardiomyocyte-specific reporter mice exposed to pressure overload by transverse aortic banding (TAB), we obtained gene expression profiles of hypertrophic (one-week TAB) and failing (eight-weeks TAB) cardiomyocytes. We identified subsets of genes differentially regulated and specific for either stage. Among these, we found upregulation of known marker genes for HF, such as Nppb and Myh7. Additionally, we identified a set of genes specifically upregulated in failing cardiomyocytes and that so far have not been studied in HF, including the platelet isoform of phosphofructokinase (PFKP). Human cardiomyocytes subjected to 7-day NE/AngII treatment recapitulated the upregulation of the failure-induced genes indicating conservation. RNA-seq on failing and healthy human hearts confirmed increased expression for several failure-induced genes and allowed for expressional correlation to NPPB/MYH7. Finally, suppression of Pfkp in PE-treated primary cardiomyocytes reduced stress-induced gene expression and hypertrophy, suggesting a role in cardiomyocyte failure. Conclusion - Using cardiomyocyte-specific transcriptomic analysis we identified novel failure-induced genes relevant for human HF, and show that PFKP is a conserved failure-induced gene that can modulate cardiomyocyte stress response.
2020-09-15 | GSE138299 | GEO
Project description:Background: Although myocardial hypertrophy is an essential component of heart’s response to many forms of stress, prolonger excessive hypertrophy contributes importantly to the pathogenesis of heart disease. The pimobendan is a drug that both inhibits phosphodiesterase 3 (PDE3) and acts as a calcium sensitizer, which has been used to treat heart failure. The effects of pimobendan on myocardial hypertrophy is controversial. Objective: This study aims to evaluate the therapeutic effect of pimobendan on myocardial hypertrophy. Methods: Mice were treated with low oral doses of pimobendan (1mg/kg/d) for 4 weeks after transaortic constriction. Heart structure and function was assessed using ultrasound, hemodynamic measurements and histology combined with biochemical assessments of myocardial hypertrophy. We also examined the effects of pimobendan (100 µM) on hypertrophy in cultured neonatal rat cardiomyocytes (NRCMs) induced by 50 µM phenylephrine (PE). Results: The doses pimobendan used in our studies had no effect on baseline contractility. Nevertheless, pimobendan administration of mice subjected to TAC decreased heart weights (normalized to either tibia length or body weight) ventricular wall thickness, cardiomyocyte sizes, myocardial fibrosis and the levels of a number of key myocardial hypertrophy markers (WHICH ONES). In cultured neonatal cardiomyocytes, pimobendan attenuated the PE-induced hypertrophy. In both hypertrophy models pimobendan reduced the phosphorylation levels of several essential proteins in the MAPK pathway, PI3K-AKT pathway, and calcineurin signaling pathway. Conclusion: Low pimobendan may attenuate myocardial hypertrophy. Although the underlying mechanisms remain to be elucidated, the MAPK pathway is likely to play a role.
2023-07-01 | GSE182501 | GEO
Project description:Zinc dyshomeostasis has been involved in the pathogenesis of cardiac hypertrophy; however, the dynamic regulation of intracellular zinc and its downstream signaling in cardiac hypertrophy remain largely unknown. Here we screened ZIP (SLC39) family members that were responsible for zinc uptake in a phenylephrine (PE)-induced cardiomyocyte hypertrophy model. We found that Slc39a2 was the only member that was altered at mRNA level by PE treatment in neonatal rat ventricular myocytes (NRVMs), but its protein level was not affected. Zincpyr1 staining showed a significant decrease in zinc uptake after PE treatment or after Slc39a2 knockdown in NRVMs, indicating an inhibition of its transport activity during hypertrophy. Slc39a2 deficiency caused spontaneous hypertrophy in NRVMs, and further exacerbated the hypertrophic responses after PE treatment. RNA sequencing analysis confirmed a largely aggravated pro-hypertrophic transcriptome reprogramming after Slc39a2 knockdown. Interestingly, the innate immune pathways, including NOD signaling, TOLL-like receptor, NFB, and IRFs, were substantially enriched after Slc39a2 knockdown. Whereas IRF7, the most sensitive among all IRFs, did not mediate the effect of Slc39a2 in hypertrophy, pro-hypertrophy phosphorylations of NFB and STAT3 were significantly enhanced after Slc39a2 knockdown, in parallel with degradation of IkBα protein. Our data demonstrate that SLC39A2-mediated zinc homeostasis contributes to the remodeling of innate immune signaling in cardiomyocyte hypertrophy, and provide novel insights into the pathogenesis of heart failure and its treatment.
2021-11-24 | GSE175884 | GEO
Project description:Pathological growth of cardiomyocytes during hypertrophy is characterized by excess protein synthesis; however, the regulatory mechanism remains largely unknown. Using a neonatal rat ventricular myocyte (NRVMs) model, here we find that the expression of nucleosome assembly protein 1 like 5 (Nap1l5) is upregulated in phenylephrine (PE)-induced hypertrophy. Knockdown of Nap1l5 expression by siRNA significantly blocks cell size enlargement and pathological gene induction after PE treatment. In contrast, Adenovirus-mediated Nap1l5 overexpression significantly aggravates the pro-hypertrophic effects of PE on NRVMs. RNA-seq analysis reveals that Nap1l5 knockdown reverses the pro-hypertrophic transcriptome reprogramming after PE treatment. Whereas immune response is dominantly enriched in the upregulated genes, oxidative phosphorylation, cardiac muscle contraction and ribosome related pathways are remarkably enriched in the down-regulated genes. Although PRC2 and PRC1 are involved in Nap1l5-mediated gene regulation, Nap1l5 does not directly alter the levels of global histone methylations. However, puromycin incorporation assay shows that Nap1l5 is both necessary and sufficient to drive the increased protein synthesis rate in cardiomyocyte hypertrophy. This is attributable to a direct regulation of ribosome assembly by Nap1l5. Our findings demonstrate a previously unrecognized role of Nap1l5 in translation control during cardiac hypertrophy.
2022-10-09 | GSE185699 | GEO
Project description:The identification of key factors involved in pathological cardiac hypertrophy is crucial to exploring novel treatments for heart failure. In this study, we elucidated the role of Ubiquitin-specific protease 29 (USP29), a deubiquitinase, in pressure overload-induced cardiac hypertrophy. Genetic knockout of USP29 in mice significantly exacerbated TAC-induced heart hypertrophy, dysfunction, and fibrosis; whereas overexpression of USP29 in cardiomyocytes attenuated the hypertrophic response. Similarly, USP29 markedly alleviated PE-induced hypertrophy of primary neonatal rat cardiomyocytes. Mechanistically, the cardio-protective effects mediated by USP29 were attributed to its suppression of transforming growth factor β-activated kinase 1 (TAK1)-JNK/P38 signaling pathway activation. Collectively, our study suggests that targeting either USP29 or its interaction with TAK1 could represent an innovative therapeutic strategy for treating heart failure and cardiac hypertrophy.
2024-04-20 | GSE263965 | GEO
Project description:An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiac cardiomyocytes, the transcription factor Gata4 is required for agonist-induced cardiomyocyte hypertrophy. We hypothesized that in the intact organism Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed upregulation of genes associated with apoptosis and fibrosis, including members of the TGF? pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure. Experiment Overall Design: We reasoned that if Gata4 was a crucial regulator of pathways necessary for cardiac hypertrophy, then modest reductions of Gata4 activity should result in an observable cardiac phenotype. To test this hypothesis, we used gene targeted mice that express reduced levels of Gata4. We characterized these mice at baseline and after pressure Experiment Overall Design: overload.
2007-11-13 | E-GEOD-5500 | biostudies-arrayexpress
Project description:Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.
2018-07-30 | GSE95142 | GEO
Project description:To determine the role of m6A methylation in the heart we isolated primary cardiomyocytes and performed m6A immunoprecipitation followed by RNA sequencing. We measured the level of m6A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6A methylation showed significant enrichment in genes that regulate kinases and intracellular signaling pathways. Inhibition of METTL3 completely abrogated the ability of cardiomyocytes to undergo hypertrophy when stimulated to grow, while increased expression of the m6A RNA methylase METTL3 was sufficient to promote cardiomyocyte hypertrophy both in vitro and in vivo. Our study identified METTL3-mediated methylation of mRNA on N6-adenosines as a dynamic modification that is enhanced in response to hypertrophic stimuli and is necessary for a normal hypertrophic response in cardiomyocytes.
2018-08-29 | GSE119170 | GEO