ACAD8 deficiency promotes pathological cardiac hypertrophy in response to pressure overload by regulating histone isobutyrylation
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ABSTRACT:
INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic, Liquid Chromatography MS - alternating - reverse-phase
PROVIDER: MTBLS14207 | MetaboLights | 2026-04-15
REPOSITORIES: MetaboLights
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Project description:Here, we performed pathological cardiac hypertrophy transcriptome analyses by using heart tissue from Sham or TAC surgery to identify the charecteric in pathological cardiac hypertrophy. In addition, through combined analysis with the aging-associated transcriptome to identify the similarity and difference between heart ageing and pathological cardiac hypertrophy.
2025-01-29 | GSE203083 | GEO
Project description:Pressure overload-induced cardiac hypertrophy and heart failure involve profound remodeling of the myocardial proteome. To elucidate the role of the E3 adaptor protein SPOP in this process, we performed TMT-based quantitative proteomic analysis on left ventricular tissues collected four weeks after transverse aortic constriction (TAC) from Myh6-Cre control mice (n=5) and cardiac-specific SPOP knockout (cKO) mice (n=5).
2025-08-26 | PXD067120 | Pride
Project description:Deubiquitinating enzymes have gained more and more attention in the field of pathological cardiac hypertrophy. In this study, we explored the role of a deubiquitinase, OTUD1, in the transverse aortic constriction (TAC) induced cardiac hypertrophy. We found the upregulation of OTUD1 in heart tissues of TAC mice. OTUD1 overexpression promoted cardiac hypertrophy, cardiac fibrosis and apoptosis. Conversely, OTUD1 depletion alleviated these pathological changes both in vivo and in vitro. Mechanistically, ASK1 was identified as one substrate of OTUD1 using co-immunoprecipitation followed with LC-MS/MS. Interestingly, OTUD1 didn’t deubiquitinate ASK1, but increased the phosphorylation level of ASK1 during the process of cardiac hypertrophy. We found that PGAM5, the upper stream regulator of ASK1, was stabilized by OTUD1 in a K63 ubiquitin chain dependent way, which reminded us OTUD1 increased the phosphorylation level of ASK1 by deubiquitinating PGAM5. This study identified the OTUD1-ASK1 axis as a potential therapeutic target for pathological cardiac hypertrophy.
2023-09-05 | GSE241809 | 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:Pathological cardiac hypertrophy is a key predisposing factor for heart failure (HF). This study investigates the role of the E3 ubiquitin ligase Tripartite Motif-Containing 40 (TRIM40) in cardiac hypertrophy. Using TRIM40 knockout (TRIM40-/-) and cardiac-specific overexpressing mice, pathological hypertrophy was induced by angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Results demonstrated that TRIM40 expression was upregulated in hypertrophic hearts. TRIM40 deficiency attenuated cardiac hypertrophy and dysfunction, whereas its overexpression exacerbated pathological remodeling. Mechanistically, TRIM40 binds Protein Kinase N2 (PKN2) via its B-box domain, promoting K63-linked ubiquitination at cysteine 29 that enhances PKN2 phosphorylation at Ser815 and activates downstream signaling. Pharmacological inhibition of PKN2 attenuated cardiac remodeling induced by TRIM40 overexpression. These findings indicate that TRIM40 promotes cardiac hypertrophy through K63-linked ubiquitination and activation of PKN2, identifying TRIM40 as a potential therapeutic target for HF.
2025-12-21 | GSE314005 | GEO
Project description:Our previous single-cell RNA sequencing study in the adult human heart revealed that cardiomyocytes from both the atrium and ventricle display high activities of Krüppel-like factor 2 (KLF2) regulons. However, the role of the transcription factor KLF2 in cardiomyocyte biology remains largely unexplored. We employed transverse aortic constriction surgery in male C57BL/6J mice to develop an in vivo model of cardiac hypertrophy, and generated different in vitro cardiac hypertrophy models in neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes. Our results demonstrated a significant reduction in KLF2 expression during the progression of cardiac hypertrophy. In vitro, KLF2 deficiency exacerbates cardiac hypertrophy and enhances hypertrophic reprogramming, while KLF2 overexpression attenuates cardiac hypertrophy and reverses hypertrophic transcriptome reprogramming. Mechanistically, combined RNA-seq and cleavage under targets & tagmentation (CUT&Tag) analysis revealed that KLF2 exerts its protective effects by directly regulating a set of genes associated with cardiac hypertrophy. In vivo, KLF2 overexpression specifically in cardiomyocytes effectively prevents TAC-induced cardiac hypertrophy in mice. Additionally, we found that simvastatin elevates KLF2 expression in cardiomyocytes, which subsequently alleviates cardiomyocyte hypertrophy. This study provides the first evidence that transcription factor KLF2 serves as a negative regulator of cardiac hypertrophy. Our findings highlight the therapeutic potential of enhancing KLF2 expression, particularly through simvastatin administration, as a promising strategy in the treatment of cardiac hypertrophy.
2025-01-01 | GSE283973 | GEO
Project description:RNA-Seq analysis of mouse cardiac transcriptome. Transverse aortic contraction was used to induce cardiac hypertrophy (TAC). To compare wild type and physiological cardiac hypertrophy 'Sendetary' (feeding mouse during 4 weeks) and 'Swim (exercise training to induce the cardiac hypertrophy) samples were analysed.
2012-05-11 | E-MTAB-727 | biostudies-arrayexpress
Project description:Pathological cardiac hypertrophy can lead to heart failure and is one of the leading causes of death globally. Understanding the molecular mechanism of pathological cardiac hypertrophy will contribute to the treatment of heart failure. Deubiquitinating enzymes (DUBs) are essential to cardiac pathophysiology by precisely controlling protein function, localization, and degradation.This study set out to investigate the role of a DUB, USP25, in pathological cardiac hypertrophy, reveal its molecular mechanism, and hopefully provide a new therapeutic target for heart failure.We revealed increased protein level of USP25 expression in the cardiomyocytes in response to Ang II stimulation. USP25 deficiency aggravated cardiac hypertrophy and cardiac dysfunction under Ang II and TAC treatment. Mechanistically, LC-MS/MS analysis combined with Co-IP was used to identify SERCA2a, an anti-hypertrophy protein, as an interacting protein of USP25. Also, our data showed that USP25 bound to SERCA2a directly via its USP domain and cysteine at position 178 of USP25 exerts deubiquitination to maintain the stability of the SERCA2a protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining calcium content in cardiomyocytes. Moreover, restoration of USP25 expression via with AAV9 vectors in USP25-/- mice attenuated Ang II-induced cardiac hypertrophy and cardiac dysfunction, whereas SERCA2a myocardial overexpression could offset the effect of USP25.
2023-03-01 | GSE221396 | GEO
Project description:Cardiac hypertrophy is characterized by an increase in heart size and profound gene expression changes. Pharmacological histone deacetylase (HDAC) inhibitors attenuate pathological cardiac remodeling and hypertrophic gene expression. Published literature has linked enzymes that mediates histone acetylation to pathogenesis, however, the role of histone acetylation to define hypertrophic gene regulatory events are not well understood. We used chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (seq) to comprehensively examine genome-wide histone acetylation changes in a pre-clinical model of pathological cardiac hypertrophy by transverse aortic constricted (TAC). We examined the gene targets conferred by the prototypical HDAC inhibitor Trichostatin A (TSA). TSA induces genome-wide histone acetylation and deacetylation in the heart. Alterations to histone acetylation were found on genes involved in cardiac morphology such as cardiac contraction, collagen deposition, inflammation and extracellular matrix. Gene set enrichment analysis identified NF-kappa B (NFKB), as a transcription factor positively correlated with TAC and negatively correlated with TSA by ChIP-seq. Histone acetylation on the promoters of NKFB target genes was increased, consistent with gene activation. In contrast, the promoters of these genes were deacetylated by TSA in hypertrophic animals and reduced expression of NFKB target genes. Our results suggest a potential mechanism for TSA mediated cardioprotection conferred by histone deacetylation of target genes implicating the importance of inflammation. ChIP-seq profiles for histone acetylation in left ventricles of mice that develop cardiac hypertrophy and treated with HDAC inhibitors were generated by deep sequencing, using Illumina GAIIx.
2015-04-25 | E-GEOD-63590 | biostudies-arrayexpress
Project description:Compelling evidence suggests that mitochondrial dysfunction contributes to the pathogenesis of heart failure, including defects in the substrate oxidation, and the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). However, whether such changes occur early in the development of heart failure, and are potentially involved in the pathologic events that lead to cardiac dysfunction is unknown. To address this question, we conducted transcriptomic/metabolomics profiling in hearts of mice with two progressive stages of pressure overload-induced cardiac hypetrophy: i) cardiac hypertrophy with preserved ventricular function achieved via transverse aortic constriction for 4 weeks (TAC) and ii) decompensated cardiac hypertrophy or heart failure (HF) caused by combining 4 wk TAC with a small apical myocardial infarction. Transcriptomic analyses revealed, as shown previously, downregulated expression of genes involved in mitochondrial fatty acid oxidation in both TAC and HF hearts compared to sham-operated control hearts. Surprisingly, however, there were very few changes in expression of genes involved in other mitochondrial energy transduction pathways, ETC, or OXPHOS. Metabolomic analyses demonstrated significant alterations in pathway metabolite levels in HF (but not in TAC), including elevations in acylcarnitines, a subset of amino acids, and the lactate/pyruvate ratio. In contrast, the majority of organic acids were lower than controls. This metabolite profile suggests “bottlenecks” in the carbon substrate input to the TCA cycle. This transcriptomic/metabolomic profile was markedly different from that of mice PGC-1a/b deficiency in which a global downregulation of genes involved in mitochondrial ETC and OXPHOS was noted. In addition, the transcriptomic/metabolomic signatures of HF differed markedly from that of the exercise-trained mouse heart. We conclude that in contrast to current dogma, alterations in mitochondrial metabolism that occur early in the development of heart failure reflect largely post-transcriptional mechanisms resulting in impedance to substrate flux into the TCA cycle, reflected by alterations in the metabolome. Microarray gene expression profiling was performed with bi-ventricle RNA isolated from (1) 3 month-old female C57Bl6/J mice with transverse aortic constriction (CH), vs sham-operated control (Sham-CH), (2) 3 month-old female C57Bl6/J mice with heart failure (HF), vs. sham-operated control (Sham-HF); (3) 2 month-old female C57Bl6/J mice with voluntary wheel training for 2 months (Run), vs. Sedentary control (Sed). Five biological replicates are included for each group.
2014-10-01 | E-GEOD-56348 | biostudies-arrayexpress