Identification of a SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis
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ABSTRACT:
PROVIDER: PRJNA1081875 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28152578_1.fastq.gz | Fastqsanger.gz | |||
| SRR28152578_2.fastq.gz | Fastqsanger.gz | |||
| SRR28152579_1.fastq.gz | Fastqsanger.gz | |||
| SRR28152579_2.fastq.gz | Fastqsanger.gz | |||
| SRR28152580_1.fastq.gz | Fastqsanger.gz |
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Project description:Sirtuin3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF) , through its deacetylation modifications. Thus, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC inhibited the mammalian target of rapamycin-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/mothers against decapentaplegic homolog 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC could enhance mitochondrial proline metabolism, inhibited ROS-p38MAPK pathway and thereby protecting against ISO-induced oxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMPK-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
2024-02-28 | GSE260489 | GEO
Project description:Myocardial hypertrophy develops when the heart is subjected to biomechanical stress, neurohormonal or hemodynamic stimuli. Isoprenaline-induced myocardial hypertrophy in mice exhibited abnormally elevated steroid receptor RNA activator (SRA) level in hypertrophic myocardium, suggesting SRA’s potential functions in hypertrophic pathogenesis. SRA knockout or cardiac-specific knockdown attenuated cardiac remodeling without impairing baseline cardiac function. RNA sequencing and mechanistic studies identified SRA as a transcriptional coactivator that enhances GR-mediated upregulation of HSP70, which in turn activates pro-hypertrophic Akt signaling. Adenoviral SRA overexpression in H9C2 cardiomyocytes amplified isoprenaline-triggered hypertrophic gene expression via this GR-HSP70-Akt axis. Those findings establish SRA as a stress-responsive regulator of maladaptive cardiac growth and propose SRA inhibition as a targeted therapeutic strategy for hypertrophy-related cardiomyopathy. This work bridges noncoding RNA biology with metabolic signaling in heart disease, offering both mechanistic insights and translational potential.
2025-06-30 | GSE300259 | GEO
Project description:Targeting steroid receptor RNA activator as a novel therapeutic strategy for myocardial hypertrophy
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Project description:Cardiac hypertrophy is a cardiac structural remodeling and dysfunction resulting from chronic hypertension and is an independent risk factor for cardiovascular morbidity and mortality. Study have implicated the protect role of oxymatrine (OMT) on the ventricular remodeling in spontaneously hypertensive rats (SHRs). However, the underlying mechanisms of remains unclear. In this study, we investigated investigates the potential of OMT in improving myocardial hypertrophy in SHRs through integrated analysis of transcriptomics and metabolomics. The results show that OMT significantly alleviates myocardial hypertrophy in SHRs and improves heart function by reducing the myocardial enlargement and collagen deposition. Transcriptomic analysis revealed that OMT reversed the expression of 10 genes associated with linoleic acid/arachidonic acid metabolism, cytochrome P450, steroid hormone biosynthesis, and myocardial adrenergic signaling. Metabolomic analysis indicated that OMT reversed the levels of 16 metabolites related to steroid hormone biosynthesis, aldosterone synthesis and secretion, and tryptophan metabolism. Integrated analysis revealed that Integrated analysis identified Cyp2e1 and desoxycortone (also known deoxycorticosterone, DOC) as key genes and metabolites involved in the transcriptional and metabolic interactions through which OMT improves myocardial hypertrophy in SHR. In summary, our study underscores the potential molecular and metabolic mechanisms of OMT against pressure overload-induced myocardial hypertrophy and provides theoretical support for its exploration in other indications.
2025-09-26 | GSE282767 | 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:SIRT5 is one of the seven members of the NAD+-dependent sirtuin family of protein deacylase that is mainly present in mitochondria and regulates metabolism. In heart, SIRT5 is highly expressed and responsible for succinylation on metabolic enzymes. Although the role of SIRT5 in maintaining cardiac homeostasis under physiological stress and few potential substrates of SIRT5 have been preliminarily revealed, the regulatory network and key cellular signaling pathways involving SIRT5 in myocardial hypertrophy remain largely unknown. Here, we used an established murine model of pressure overload-induced myocardial hypertrophy caused by transverse aortic constriction (TAC) to outline the network and pathway involving SIRT5 in cardiac stress responses. Remarkably, SIRT5 KO mice had enhanced myocardial hypertrophy after TAC surgery compared with wild-type mice.
2024-10-05 | GSE186985 | GEO
Project description:NSUN2 mediated m5C modification regulates myocardial hypertrophy
| PRJNA981449 | ENA
Project description:Vitamin B12 alleviates myocardial ischemia/reperfusion injury
| PRJNA933927 | ENA
Project description:Background: Exercise can induce physiological myocardial hypertrophy (PMH), and former athletes can live 5-6 years longer than nonathletic controls, suggesting a benefit after regression of PMH. We previously reported that regression of pathological myocardial hypertrophy has antihypertrophic effects. Accordingly, we hypothesized that antihypertrophic memory exists even after PMH has regressed, increasing myocardial resistance to subsequent pathological hypertrophic stress. Methods and Results: C57BL/6 mice were submitted to 21 days of swimming training to develop PMH. After termination of exercise, PMH regressed within 1 week. PMH regression mice (hypertrophic preconditioning group, EHP) and sedentary mice (control group) then underwent transverse aortic constriction (TAC) or a sham operation. At 1 and 4 weeks after TAC, the EHP group showed less increase in myocardial hypertrophy and lower expression of the Nppa and Myh7 genes than the sedentary group. At 4 weeks after TAC, EHP mice had less pulmonary congestion, smaller left ventricular dimensions and end-diastolic pressure, and a larger left ventricular ejection fraction and maximum pressure change rate than sedentary mice. Quantitative polymerase chain reaction (qPCR) revealed that the long noncoding myosin heavy chain associated RNA transcript Mhrt779 was one of the markedly upregulated long noncoding RNAs in the EHP group. Silencing of Mhrt779 attenuated the antihypertrophic effect of EHP in mice with TAC and in cultured cardiomyocytes treated with angiotensin II, and overexpression enhanced the antihypertrophic effect. By chromatin immunoprecipitation assay and qPCR, we found that EHP increased histone 3 trimethylation (H3K4me3 and H3K36me3) at a4 promoter of Mhrt779. Comprehensive identification of RNA-binding proteins by mass spectrometry and Western blot showed that Mhrt779 can bind Brg1 to upregulate Hdac2 and inhibit phosphorylation of Akt and GSK3β. Conclusions: Myocardial hypertrophy preconditioning evoked by exercise increases resistance to pathological stress via an antihypertrophic effect mediated by a signal pathway of Mhrt779 /Hdac2/p-Akt/p-GSK3β.
2020-11-07 | GSE161030 | GEO
Project description:Role of SIRT5 in Inhibition of Myocardial Hypertrophy
| PRJNA777232 | ENA