RyR2 inhibitor attenuates cardiac hypertrophy by downregulating TNF-α/NF-κB/NLRP3 signaling pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA766092 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16059850_1.fastq.gz | Fastqsanger.gz | |||
| SRR16059850_2.fastq.gz | Fastqsanger.gz | |||
| SRR16059851_1.fastq.gz | Fastqsanger.gz | |||
| SRR16059851_2.fastq.gz | Fastqsanger.gz | |||
| SRR16059852_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Cardiac Ryanodine receptors (RyR2) can regulate Ca2+ release in the excitation-contraction coupling, when activated, it releases a large amount of Ca2+ into the cytoplasm. Additionally, studies have shown that dantrolene (a RyR2 inhibitor) protects against heart failure and arrhythmias by inhibiting domain decompression, Ca2+ leakage and diastolic Ca2+ sparking. However, the role and mechanism of dantrolene in cardiac hypertrophy remain unclear. Objective: In this study, we aimed to evaluate the therapeutic effects of dantrolene on pressure overload-induced cardiac hypertrophy in mice models by transverse aortic contraction (TAC) surgery and to explore its potential mechanism. Methods: C57/B6 mice (age: 8 weeks) underwent TAC or sham surgical procedure and were administered oral dantrolene (30 mg/kg) or the solvent drug postoperatively. After 4 weeks of drug treatment, RNA sequencing of mice left ventricle was performed.qRT–PCR validation was performed using SYBR Green assays. Results: We found that dantrolene significantly alleviated TAC-induced cardiac hypertrophy. According to RNA sequencing, 184 down-regulated genes were found after dantrolene treatment compared with TAC group, 8 of these were validated with qRT–PCR. According to the KEGG analysis, Creb3l3, IL18R1 and Ccl5 were down-regulated after dantrolene treatment, which were related to TNF-α pathway. Conclusion: As a RyR2 inhibitor, dantrolene attenuates cardiac hypetrophy through downregulating the TNF-α/NF-κB/NLRP3 signaling pathway.
2023-07-01 | GSE184769 | GEO
Project description:Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. Here, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old wildtype mice, and in a mouse model of tauopathy. We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and tauopathy mice. These effects of NF-κB/NLRP3-targeting Nanoligomer treatment were associated with reduced glial cell activation in old wildtype mice, less pathology in tauopathy mice, favorable changes in transcriptome signatures of inflammation (reduced) and neuronal health (increased) in both mouse models, and no adverse systemic effects. Collectively, our results provide a basis for future translational studies targeting NF-κB/NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegenerative disease.
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Project description:Ursolic acid-induced DECR1 degradation via NF-κB/NLRP3 pathway inihibits vascular calcification
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Project description:We investigated the novel molecular mechanisms of the antioxidant and anti-inflammatory properties of S-allylmercaptocysteine (SAMC) based on a transcriptomic study in a non-alcoholic fatty liver disease (NAFLD) rat model. NAFLD was induced in Sprague-Dawley rats by feeding with a high fat diet (HFD) for 12 weeks. 200mg/kg SAMC was fed by oral gavage for 4 weeks from 9-12 week. We found that SAMC co-administration attenuated HFD-induced liver injury, including the increased serum ALT, hepatic oxidative stress and inflammation. Transcriptomic analysis revealed that SAMC dramatically induced the XRE- and ARE-driven drug metabolising enzymes (DMEs) including Akr7a3, Akr1b8, and NQO1. The nuclear translocation of the upstream regulator of xenobiotics metabolism, AhR, and regulator of antioxidant responses, Nrf2, were significantly increased by SAMC treatment. Furthermore, SAMC counteracted the effects of HFD on NF-κB/IκB and NLRP3/6 pathways with decreasing protein levels of ASC, cleaved caspase-1, IL-18 and IL-1β. These results were further verified in another mice NASH model induced by an MCD diet with SAMC co-administration. Conclusion: we propose that SAMC triggers AhR/Nrf2-mediated antioxidant responses which may further suppress the NLRP3/6 inflammasome pathway and NF-κB activation, contributing to the improvement of NAFLD/NASH.
2020-07-20 | GSE150841 | 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: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:Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear. Mice were treated with TMAO in normal saline by oral gavage for 14 consecutive days. Then, mice were made into MCAO models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were assessed. Since microglia played a crucial role in stroke, microglia of MCAO mice were isolated for high-throughput sequencing to identify the most differentially expressed gene following TMAO treatment. Afterward, the downstream pathways of TMAO were investigated using primary microglia. Our results demonstrated that TMAO promoted the release of inflammatory cytokines in the brain of MCAO mice and promoted the activation of OGD/R microglial inflammasome, thereby exacerbating stroke outcomes. FTO/IGF2BP2 inhibited NLRP3 inflammasome activation in OGD/R microglia by downregulating the m6A level of NLRP3, TMAO can inhibit the expression of FTO and IGF2BP2, thus promoting the activation of NLRP3 inflammasome in OGD/R microglia. In conclusion, these results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in stroke through FTO/IGF2BP2.
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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.
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Project description:Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy
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