The calcineurin splicing variant CnAb1 reduces pressure overload-induced cardiac hypertrophy by promoting mitohormesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE79536 | GEO | 2019/03/01
REPOSITORIES: GEO
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Project description:Aortic banding is an excellent model system to evaluate the process of development of left ventricular hypertrophy in response to hemodynamic stress. The Affymetrix GeneChip MgU74Av1 was used to analyze expression profiles of mice at different time points after surgical intervention for pressure-overload induced hypertrophy. More information about this model may be obtained at http://cardiogenomics.med.harvard.edu/groups/proj1/pages/band_home.html Keywords = Pressure overload, cardiac hypertrophy Keywords: time-course
2002-07-30 | GSE76 | GEO
Project description:We have previously found that overexpression of CHF1/Hey2 in the myocardium prevents the development of phenylephrine-induced hypertrophy. To determine the role of CHF1/Hey2 in pressure overload hypertrophy, we performed ascending aortic banding on wild type and transgenic mice overexpressing CHF1/Hey2 in the myocardium. We found that both wild type and transgenic mice developed increased ventricular weight to body weight ratios one week after aortic banding. Wild type mice also developed decreased fractional shortening after one week when compared to preoperative echocardiograms and sham operated controls. Transgenic mice, in comparison, demonstrated preserved fractional shortening. Histological examination of explanted heart tissue demonstrated extensive fibrosis in wild type hearts, but minimal fibrosis in transgenic hearts. TUNEL staining demonstrated increased apoptosis in the wild type hearts but not in the transgenic hearts. Exposure of cultured neonatal myocytes from wild type and transgenic animals to hydrogen peroxide, a potent inducer of apoptosis, demonstrated increased apoptosis in the wild type cells. Gene Set Analysis of microarray data from wild type and transgenic hearts one week after banding revealed suppression and activation of multiple pathways involving apoptosis, cell signaling and biosynthesis. These findings demonstrate that CHF1/Hey2 promotes physiological over pathological hypertrophy in pressure overload through suppression of apoptosis and global regulation of multiple transcriptional pathways.
2010-01-20 | GSE13031 | GEO
Project description:Inhibitors of DNA methyl transferase (DNMT) might be useful for treating cardiac hypertrophy by preventing de novo methylation and reduced transcription of anti-hypertrophic genes. This approach had been tested, but without a detailed phenotypic and methylation analysis. Here, we subjected rats to pressure overload and treatment with the DNMT inhibitor N-phthalyl-L-tryptophan (RG108) and analysed DNA methylation by cardiomyocyte (CM)-specific reduced representation bisulphite sequencing (RRBS).
2019-03-07 | GSE111513 | GEO
Project description:Pathological cardiac hypertrophy, a dynamic remodeling process, is a major risk factor for heart failure. Although a number of key regulators and related genes have been identified, how the transcription factors (TFs) dynamically regulate the associated genes and control the morphological and electrophysiological changes during the hypertrophic process are still largely unknown. In this study, we obtained the time-course transcriptomes at five time points in four weeks from male murine hearts subjected to transverse aorta banding surgery. From a series of computational analyses, we identified three major co-expression modules of TF genes that may regulate the gene expression changes during the development of cardiac hypertrophy in mice. After pressure overload, the TF genes in Module 1 were up-regulated before the occurrence of significant morphological changes and one week later were down-regulated gradually, while those in Modules 2 and 3 took over the regulation as the heart size increased. Our analyses revealed that the TF genes up-regulated at the early stages likely initiated the cascading regulation and most of the well-known cardiac miRNAs were up-regulated at later stages for suppression. In addition, the constructed time-dependent regulatory network reveals some TFs including Egr2 as new candidate key regulators of cardiovascular-associated (CV) genes.
2017-05-31 | GSE99459 | GEO
Project description:Pathological cardiac hypertrophy, a dynamic remodeling process, is a major risk factor for heart failure. Although a number of key regulators and related genes have been identified, how the transcription factors (TFs) dynamically regulate the associated genes and control the morphological and electrophysiological changes during the hypertrophic process are still largely unknown. In this study, we obtained the time-course transcriptomes at five time points in four weeks from male murine hearts subjected to transverse aorta banding surgery. From a series of computational analyses, we identified three major co-expression modules of TF genes that may regulate the gene expression changes during the development of cardiac hypertrophy in mice. After pressure overload, the TF genes in Module 1 were up-regulated before the occurrence of significant morphological changes and one week later were down-regulated gradually, while those in Modules 2 and 3 took over the regulation as the heart size increased. Our analyses revealed that the TF genes up-regulated at the early stages likely initiated the cascading regulation and most of the well-known cardiac miRNAs were up-regulated at later stages for suppression. In addition, the constructed time-dependent regulatory network reveals some TFs including Egr2 as new candidate key regulators of cardiovascular-associated (CV) genes.
2017-05-31 | GSE99458 | GEO
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
Project description:AimsCyclic GMP (cGMP)-specific phosphodiesterase 5 (PDE5) inhibition by sildenafil (SIL) activates myocardial cGMP-dependent protein kinase G (PKG) and blunts cardiac hypertrophy. To date, the only documented target of PKG in myocardium is the serine-threonine phosphatase calcineurin (Cn), which is central to pathological cardiac hypertrophy. We tested whether Cn suppression is necessary in order to observe anti-hypertrophic effects of SIL.Methods and resultsMice lacking the Cn-Abeta subunit (CnAbeta(-/-)) and wild-type (WT) controls were subjected to transverse aorta constriction (TAC) with or without SIL (200 mg/kg/day, p.o.) for 3 weeks. TAC-induced elevation of Cn expression and activity in WT was absent in CnAbeta(-/-) hearts, and the latter accordingly developed less cardiac hypertrophy (50 vs. 100% increase in heart weight/tibia length, P < 0.03) and chamber dilation. SIL remained effective in CnAbeta(-/-) mice, increasing PKG activity similarly as in WT, suppressing hypertrophy and fetal gene expression, and enhancing heart function without altering afterload. TAC-stimulated calcium-calmodulin kinase II, Akt, and glycogen synthase kinase 3beta in both groups (the first rising more in CnAbeta(-/-) hearts), and SIL also suppressed these similarly. Activation of extracellular signal-regulated kinase observed in WT-TAC but not CnAbeta(-/-) hearts was also suppressed by SIL.ConclusionPDE5A inhibition and its accompanying PKG activation blunt hypertrophy and improve heart function even without Cn activation. This occurs by its modulation of several alternative pathways which may result from concomitant distal targeting, or activity against a common proximal node.
| S-EPMC2721646 | biostudies-literature
Project description:Expression profiling of hearts from FVB males subjected to cardiac pressure overload by transverse aortic constriction (TAC). TAC performed on 8-10 weeks month old males and females. Hearts examined 30 weeks after surgery. Keywords: ordered
2005-06-29 | GSE2459 | GEO
Project description:Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload-induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and ?-myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4 pathway and suppression of the interaction of Orai1/STIM1.
| S-EPMC5571547 | biostudies-literature
Project description:Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease but the significance of HINT2 in cardiac hypertrophy remains unknown. Therefore, the current study aims to determine the role of HINT2 in cardiac remodeling. HINT2 expression was found to be lower in failing hearts and hypertrophic cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocytes hypertrophy and cardiac dysfunction in response to stress. Conversely, the deficiency of HINT2 in the heart of mice resulted in a worsened hypertrophic phenotype. Further analysis indicated that the upregulated genes were primarily associated with the oxidative phosphorylation and mitochondrial complex I pathway in the HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 upregulated the expression of NDUFs genes. In cellular studies, the protective effect of overexpressing HINT2 was nullified. Lastly, we predicted that THRB might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac hypertrophy by depending on the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic intervention for reducing cardiac remodeling.
2024-06-01 | GSE260663 | GEO