Puerarin attenuates isoproterenol‑induced myocardial hypertrophy via inhibition of the Wnt/β‑catenin signaling pathway

Wang, Xiaoying; He, Kai; Ma, Linlin; Wu, Lan; Yang, Yan; Li, Yanfei

doi:10.3892/mmr.2022.12822

Cited by 2 publications

(1 citation statement)

References 95 publications

(98 reference statements)

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“…1 Myocardial hypertrophy is a pathological compensatory response to cardiac dysfunction or injury that is closely associated with chronic HF. [2][3][4] Additionally, myocardial hypertrophy is well known to play an important role in the progression of pathological cardiac remodeling, which can manifest as abnormal myocardial fibrosis. [5][6][7] The pathological mechanisms of HF are complicated and remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

Peng,

Liao,

Jin

et al. 2024

Sig Transduct Target Ther

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Sirtuin 3 (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. Accordingly, 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 was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/ small mother against decapentaplegic 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 was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (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.

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Section: Introductionmentioning

confidence: 99%

2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

Peng,

Liao,

Jin

et al. 2024

Sig Transduct Target Ther

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Exploring the Potential Pharmacological Basis and Mechanism of HJT Activity in the Treatment of CHD Based on UPLC-QE-MS and Network Pharmacology

Qi,

Jianyuan,

Wenxia

et al. 2024

Natural Product Communications

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Objective To identify the blood-entering components of HanJing Decoction (HJT) after administration based on UPLC-QE-MS/MS, and the key components, therapeutic targets and mechanisms of HJT therapeutic coronary heart disease (CHD) were analyzed using network pharmacology and molecular docking. Method The UPLC-QE-MS/MS was used to analyze the blood-entering components of HJT before and after administration. The targets of blood-entering components were predicted by SwissTargetPrediction. Targets related to CHD were collected using multiple databases. The GO and KEGG enrichment analyses were used to predict the mechanisms of HJT therapeutic CHD, and PPI and “Components-Targets-Pathways” network were used to identify and elucidate the core targets. The key blood-entering components aimed at the core target are screened by molecular docking and QSAR analysis. Results A total of 14 blood-entering components were detected in serum samples of rat after administration, and the 32 potential targets of HJT therapeutic CHD were screened out. The result of PPI network showed that the core targets of HJT for the treatment of CHD include MMP1, GSK3B, EGFR and PTGS2, and the 5 key components with high degree were screened out. The GO and KEGG enrichment analyses indicate that HJT therapy for CHD is associated with the IL-17 and cGMP-PKG signaling pathways. The result of molecular docking indicate that the binding energy of coroglaucigenin to PTGS2 is the largest and it may be the key pharmacological component of HJT, and the QSAR analysis showed that Boldine and Coroglaucigenin had excellent activity in inhibiting PTGS2. Conclusions In this study, the blood-entering components of HJT were preliminarily identified, Combined network pharmacology and molecular docking analyses revealed that the PTGS2 may be a core target, and the IL-17 and cGMP-PKG signaling pathways may be the key pathways. Moreover, the coroglaucigenin and boldine may be the key pharmacological components of HJT.

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Puerarin attenuates isoproterenol‑induced myocardial hypertrophy via inhibition of the Wnt/β‑catenin signaling pathway

Cited by 2 publications

References 95 publications

2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis

Exploring the Potential Pharmacological Basis and Mechanism of HJT Activity in the Treatment of CHD Based on UPLC-QE-MS and Network Pharmacology

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