Dataset Information

Identification of a SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE260489 | GEO | 2024/02/28

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Backgound: Cardiac pressure overload, for example in patients with aortic stenosis, induces irreversible damage in the myocardium leading to cardiac dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis. We therefore hypothesized that insufficient cardiac regeneration might contribute to the progression of pressure overload dependent disease. Here, we aimed to elucidate whether pressure overload in the regenerative stage shortly after birth could lead to a more adaptive cardiac response than in the non-regenerative stage in mice.nTAC in the non-regenerative stage induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, during induction of nTAC in the regenerative stage, cardiac function remained intact and this was associated with enhanced myocardial angiogenesis and innervation as well as increased cardiomyocyte proliferation, but neither hypertrophy nor fibrosis. Mechanistically, inhibition of cardiomyocyte proliferation and angiogenesis in nTAC in the regenerative phase by rapamycin triggered mortality and myocardial fibrosis, which both also similarly occurred upon inhibition of angiogenesis by PTK787, suggesting that both processes are essential for the adaptive cardiac response to nTAC. A comparative genome-wide transcriptomic analysis between hearts after nTAC in the regenerative versus the non-regenerative stage defined differentially expressed functional gene classes, and a related bioinformatics analysis suggested the transcription factor GATA4 as master regulator of the regenerative gene-program. Indeed, cardiomyocyte specific deletion of GATA4 converted the regenerative nTAC into a non-regenerative, maladaptive response.tablished a new model of neonatal pressure-overload in mice, which when applied in the regenerative postnatal stage, triggers a purely adaptive myocardial response. Employing this model to identify new regulators might lead to novel therapeutic strategies to combat pressure overload induced myocardial disease.

Dataset Information

Identification of a SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure