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Effect of lincRNA-p21 knockdown on neonatal mouse cardiomyocytes (CMs) treated with phenylephrine (PE)

ABSTRACT: Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. The role of cardiac long non-coding RNAs in cardiac hypertrophy and cardiomyopathy is not well understood. lincRNA-p21 was induced in mouse and human cardiomyopathy tissue. Global and cardiac-specific lincRNA-p21 knockout significantly suppressed pressure overload-induced ventricular wall thickening, stress marker elevation, and deterioration of cardiac function. Genome-wide transcriptome analysis and transcriptional network analysis revealed that lincRNA-p21 acts in trans to stimulate the NFAT/MEF2 pathway. Mechanistically, lincRNA-p21 bound to the scaffold protein KAP1. lincRNA-p21 cardiac-specific knockout suppressed stress-induced nuclear accumulation of KAP1, and KAP1 knockdown attenuated cardiac hypertrophy and NFAT activation. KAP1 positively regulated pathological hypertrophy by physically interacting with NFATC4 to promote the overactive status of NFAT/MEF2 signaling. Importantly, GapmeR ASO depletion of lincRNA-p21 similarly inhibited cardiac hypertrophy and adverse remodeling, highlighting the therapeutic potential of inhibiting lincRNA-p21.

ORGANISM(S): Mus musculus

PROVIDER: GSE262892 | GEO | 2024/06/11

REPOSITORIES: GEO

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H3K9me3 and H3K27me3 genomic occupancy on neonatal mouse cardiomyocytes (CMs) treated with PBS/phenylephrine (PE) and lincRNA-p21 WT/knockdown

Project description:Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. The role of cardiac long non-coding RNAs in cardiac hypertrophy and cardiomyopathy is not well understood. lincRNA-p21 was induced in mouse and human cardiomyopathy tissue. Global and cardiac-specific lincRNA-p21 knockout significantly suppressed pressure overload-induced ventricular wall thickening, stress marker elevation, and deterioration of cardiac function. Genome-wide transcriptome analysis and transcriptional network analysis revealed that lincRNA-p21 acts in trans to stimulate the NFAT/MEF2 pathway. Mechanistically, lincRNA-p21 bound to the scaffold protein KAP1. lincRNA-p21 cardiac-specific knockout suppressed stress-induced nuclear accumulation of KAP1, and KAP1 knockdown attenuated cardiac hypertrophy and NFAT activation. KAP1 positively regulated pathological hypertrophy by physically interacting with NFATC4 to promote the overactive status of NFAT/MEF2 signaling. Importantly, GapmeR ASO depletion of lincRNA-p21 similarly inhibited cardiac hypertrophy and adverse remodeling, highlighting the therapeutic potential of inhibiting lincRNA-p21.

2024-06-11 | GSE262936 | GEO

Effect of lincRNA-p21 knockout (KO) in ventricles 8 weeks after sham/Transverse aortic restriction (TAC) surgeries

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Project description:Pressure overload cardiac hypertrophy

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Transcription profiling of mouse IL-18 knockouts vs. wild types treated with pressure overload to examine cardiac hypertrophy

Project description:Pressure overload-induced cardiac hypertrophy was examined in IL-18 knockout and littermate control mice. Experiment Overall Design: 4 groups with RNA pooled from 5-6 per group. Role of IL-18 on gene expression in cardiac hypertrophy induced by pressure overload (transaortic constriction)

2008-06-13 | E-GEOD-5129 | biostudies-arrayexpress

The E3 ubiquitin ligase HectD3 is a novel regulator of cardiac hypertrophy and inflammation

Project description:The HECT domain E3 ubiquitin protein ligase 3 (HectD3) is highly expressed in the heart, but its cardiac function is still unknown. Here, we identified SUMO2 and Stat1 as novel cardiac substrates for HectD3. SUMO2 is a potent inducer of Calcineurin-NFAT mediated cardiomyocyte hypertrophy, whereas, Stat1 is an interferon responsive transcription factor that plays crucial role in cellular immune responses. HectD3 overexpression on one hand attenuated SUMO2-Calcineurin-NFAT signaling driven cardiomyocyte hypertrophy, on the other hand, it abrogated the pro-inflammatory actions of LPS or interferon-γ in cardiomyocytes in vitro. Consistently, AAV9-mediated overexpression of HectD3 in mice in vivo not only reduced cardiac SUMO2/Stat1 levels and pathological hypertrophy but also alleviated macrophage infiltration and fibrosis induced by pressure overload. In conclusion, we describe a novel cardioprotective mechanism involving the ubiquitin ligase HectD3, which exerts anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and Stat1.

2021-09-09 | PXD020843 | Pride

Mus musculus

Project description:Pressure-Overload Induced Cardiac Hypertrophy

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Loss of heat shock protein HSPA4 aggravates pressure overload-induced myocardial damage

Project description:Failure of molecular chaperones to direct the correct folding of newly synthesized proteins leads to the accumulation of misfolded proteins in cells. HSPA4 is a member of the heat shock protein 110 family (HSP110) that acts as a nucleotide exchange factor of HSP70 chaperones. We found that the expression of HSPA4 is upregulated in murine hearts subjected to pressure overload and in failing human hearts. To investigate the cardiac function of HSPA4, Hspa4 knockout (KO) mice were generated and exhibited cardiac hypertrophy and fibrosis. Hspa4 KO hearts were characterized by a significant increase in heart weight/body weight ratio, elevated expression of hypertrophic and fibrotic gene markers, and concentric hypertrophy with preserved contractile functions. Cardiac hypertrophy in Hspa4 KO hearts was associated with enhanced activation of gp130-STAT3, CaMKII, and calcineurin-NFAT signaling. Further analyses revealed a significant increase in cross sectional area of cardiomyocytes, and in expression levels of hypertrophic markers in cultured neonatal Hspa4 KO cardiomyocytes suggesting that the hypertrophy of mutant mice was a result of primary defects in cardiomyocytes. Gene expression profile in hearts of 3.5-week-old mice revealed a differentially expressed gene sets related to ion channels and stress response. Taken together, these results reveal that HSPA4 is implicated in protection against pressure overload-induced heart failure. Total RNA was extracted from heart ventricles of 3.5-week-old Hspa4+/+ and Hspa4-/- males (n = 3 mice for each genotype).

2012-10-10 | E-GEOD-32885 | biostudies-arrayexpress

Transcription profiling of mouse pressure overload induced cardiomyopathy time series

Project description:Expression profiles at various time points after surgical intervention for pressure-overload induced cardiac hypertrophy and failure.

2004-06-30 | E-MEXP-105 | biostudies-arrayexpress

Loss of Lin28a Attenuates Cardiac Hypertrophy Induced by Pressure Overload

Project description:Pathological cardiac hypertrophy is a major risk factor for the development of heart failure and sudden cardiac death, yet the molecular mechanism of cardiac hypertrophy is not fully understood. Recently, we found that the expression of Lin28a, a RNA-binding protein, was significantly upregulated during the early stages of cardiac hypertrophy. Interestingly, cardiac specific conditional deletion of Lin28a blunted pressure overload-induced cardiac hypertrophic responses. Given that Lin28a can bind to diverse mRNA to regulate their abundance and/or translation, we conducted RNA-seq to profile the cardiac transcriptome alteration without Lin28a under pressure overload. It showed that metabolic pathways, including glycolysis and biosynthetic pathway, were remarkedly affected. Thus, our study identifies Lin28a as a crucial regulator of cardiac hypertrophy via its role in metabolic programming.

2019-04-30 | GSE106897 | GEO

BMPER regulates cardiomyocyte size and vessel density in vivo

Project description:Background: BMPER, an orthologue of Drosophila melanogaster crossveinless-2, is a secreted factor that regulates BMP activity in endothelial cell precursors and during early cardiomyocyte differentiation. Although previously described in the heart, the role of Bmper in cardiac development and function remained unknown. Methods: BMPER deficient hearts were phenotyped histologically and functionally using echocardiography and Doppler analysis. Since BMPER -/- mice die perinatally, BMPER +/- mice were then challenged to pressure overload induced cardiac hypertrophy and hind limb ischemia to determine changes in angiogensis and regulation of cardiomyocyte size. Results: We identified for the first time the cardiac phenotype associated with BMPER haploinsufficiency. BMPER mRNA and protein are present in the heart during cardiac development through at least E14.5 but is lost by E18.5. BMPER +/- ventricles are thinner and less compact than sibling wild-type hearts. In the adult, BMPER +/- hearts present with decreased anterior and posterior wall thickness, decreased cardiomyocyte size, and an increase in cardiac vessel density. Despite these changes, BMPER +/- mice respond to pressure overload-induced cardiac hypertrophy challenge largely to the same extent as wild-type mice. Conclusion: BMPER appears to play a role in regulating both vessel density and cardiac development in vivo; however, BMPER haploinsufficiency does not result in marked effects on cardiac function or adaptation to pressure overload hypertrophy. Unpaired, two-condition experiment, wild-type vs BMPER+/- adult hearts. Biological replicates: 4 per condition.

2012-09-20 | E-GEOD-40983 | biostudies-arrayexpress

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