Qishen granule attenuates cardiac fibrosis by regulating TGF-β /Smad3 and GSK-3β pathway

Zeng, Zheng-pei; Wang, Qiyan; Yang, Xiaomin; Ren, Yinglu; Jiao, Shihong; Zhu, Qingqing; Guo, Dongqing; Xia, Kai; Wang, Yong; Li, Chun; Wang, Wei

doi:10.1016/j.phymed.2019.152949

Cited by 78 publications

(35 citation statements)

References 37 publications

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“…A previous study demonstrated that activation of the AKT pathway facilitated ECM synthesis 31 and the proliferation of CFs exposed to hypoxia 40 . Furthermore, numerous studies have shown that inhibiting the AKT pathway alleviated cardiac fibrosis 41‐44 . Our study, which showed that hypoxic CFs had a reduced PTEN expression, increased phosphorylation of PI3K, AKT, and GSK‐3β, and elevated collagen levels, was consistent with the study by Gao et al 40 Based on Wang et al's 33 observation that SOX9 regulated PI3K/AKT activity in esophageal cancer, we hypothesized that SOX9 also regulated this pathway in CFs.…”

Section: Discussionsupporting

confidence: 90%

“…40 Furthermore, numerous studies have shown that inhibiting the AKT pathway alleviated cardiac fibrosis. [41][42][43][44] Our study, which showed that hypoxic CFs had a reduced PTEN expression, increased phosphorylation of PI3K, AKT, and GSK-3β, and elevated collagen levels, was consistent with the study by Gao et al 40 Based on Wang et al's 33 observation that SOX9 regulated PI3K/AKT activity in esophageal cancer, we hypothesized that SOX9 also regulated this pathway in CFs. Our study showed that SOX9 negatively regulated PTEN and promoted PI3K, AKT, and GSK-3β signaling and collagen I/III secretion.…”

Section: Discussionsupporting

confidence: 89%

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miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

Cui¹,

Liu²,

Bo³

et al. 2020

J of Cellular Biochemistry

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Myocardial infarction (MI) will inevitably result in cardiac fibrosis. In this study, we investigated the effect of microRNA-145 (miR-145) and transcription factor sex-determining region Y box 9 (SOX9) in the production of cardiac fibrosis induced by MI. MI rat models were established by left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD, the cardiac fibrosis level was assessed by Masson's trichrome staining. Cardiac fibroblasts (CFs) exposed to hypoxia were used to simulate MI-induced fibrosis. Flow cytometry, cell counting kit-8, and transwell assays were used to examine changes in CF apoptosis, proliferation, and migration, respectively. miR-145 expression was measured by quantitative real-time polymerase chain reaction. Immunofluorescence and Western blot analysis were performed to determine the relative expression of proteins. In comparison to the sham-operated group, the expression of miR-145 was significantly downregulated in the infarction peripheral area, whereas, SOX9 was upregulated. In the infarcted heart, the overexpression of miR-145 significantly ameliorated cardiac fibrosis and cardiac function, and there was a negative correlation between miR-145 and SOX9 expressions in hypoxic CFs in vitro. In addition, SOX9 was verified to be a functional target of miR-145. Overexpression of miR-145 or inhibition of SOX9 decreased CF proliferation, migration, and fibrosis, but augmented their apoptotic rate. Moreover, the upregulation of miR-145 or suppression of SOX9 inhibited AKT and β-catenin signaling in hypoxic CFs. Taken together, this study highlights a potential treatment for cardiac fibrosis through the targeted regulation of SOX9 by miR-145, and our findings indicate that miR-145 exerts anti-fibrotic effects in MI via the negative regulation of SOX9 and its downstream AKT/GSK-3β/β-catenin pathways.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

Cui¹,

Liu²,

Bo³

et al. 2020

J of Cellular Biochemistry

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“…QSG has been demonstrated to improve myocardial energy metabolism by regulating FA and glucose metabolism in the rat model of HF induced by AMI in this study. In our previous studies, we have established stable injury models of cardiomyocytes and fibroblasts in vitro [15,43]. We will explore the regulatory mechanism of QSG on the energy metabolism of cardiomyocytes and myocardial fibroblasts, and endeavor to find out which compounds in QSG can regulate the targets of myocardial energy metabolism in the future study.…”

Section: Qsg Protected Mitochondrial Function In Hfmentioning

confidence: 99%

Qishen granules exerts cardioprotective effects on rats with heart failure via regulating fatty acid and glucose metabolism

et al. 2020

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Background: Qishen granules (QSG) has been applied to treat heart failure (HF) for decades. Our previous transcriptomics study has suggested that Qishen granules (QSG) could regulate the pathways of cardiac energy metabolism in HF, but the specific regulatory mechanism has not yet been clarified. This study was to investigate the potential mechanism of QSG in regulating myocardial fatty acid (FA) and glucose metabolism in a rat model of HF. Methods:The model of HF was induced by left anterior descending coronary artery ligation. Cardiac structure and function were assessed by cine magnetic resonance imaging (MRI) and echocardiography. Level of glucose metabolism was non-invasively evaluated by 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). Blood lipid levels were determined by enzymatic analysis. The mitochondrial ultrastructure was observed with a transmission electron microscope. The critical proteins related to FA metabolism, glucose metabolism and mitochondrial function were measured by western blotting. The ANOVA followed by a Fisher's LSD test was used for within-group comparisons.Results: QSG ameliorated cardiac functions and attenuated myocardial remodeling in HF model. The levels of serum TC, TG and LDL-C were significantly reduced by QSG. The proteins mediating FA uptake, transportation into mitochondria and β-oxidation (FAT/CD36, CPT1A, ACADL, ACADM, ACAA2 and SCP2) as well as the upstreaming transcriptional regulators of FA metabolism (PPARα, RXRα, RXRβ and RXRγ) were up-regulated by QSG. As to glucose metabolism, QSG inhibited glycolytic activity by decreasing LDHA, while stimulated glucose oxidation by decreasing PDK4. Furthermore, QSG could facilitate tricarboxylic acid cycle, promote the transportation of ATP from mitochondria to cytoplasm and restore the mitochondrial function by increasing SUCLA2, CKMT2 and PGC-1α and decreasing UCP2 simultaneously.Conclusion: QSG improved myocardial energy metabolism through increasing FA metabolism,inhibiting uncoupling of glycolysis from glucose oxidation. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

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“…The extract of Xin Jia Xuan Bai Cheng Qi decoction was found to alleviate a bleomycin-induced model of pulmonary fibrosis in rats by inhibiting TGF- β 1 and Smad2 expression, while increasing the activation of Smad7 [ 14 ]. Likewise, Qishen granules were found to attenuate cardiac fibrosis by inhibiting the TGF- β /Smad3 pathway [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Traditional Chinese medicine herbal formulae are characterized by a holistic concept and generations of development [12]. Several traditional herbal medicines used to treat fibrosis have been found to function by subduing the TGF-β1/Smad pathway [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Tiaoshen Tongluo Attenuates Fibrosis by Modulating the TGF-β1/Smad Pathway in Endometrial Stromal Cells and a Rat Model of Intrauterine Adhesion

Niu

Miao

Zhan

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Intrauterine adhesion (IUA) is a serious complication caused by excessive fibrosis resulting from endometrial repair after trauma. The traditional Chinese medicine Tiaoshen Tongluo recipe (TTR) contains ingredients associated with the alleviation of fibrosis. The transforming growth factor-β1 (TGF-β1)/Smad pathway is thought to mediate fibrosis in IUA. In this study, we evaluated the influence of TTR on endometrial fibrosis in a rat model of IUA and in TGF-β1-stimulated endometrial stromal cells (ESCs). TTR was found to alleviate the level of endometrial fibrosis in a rat model of IUA. A higher number of collagen fibers and greater damage were observed in the endometrial tissue of untreated rats compared to those treated with TTR. The expression of TGF-β1, Smad2, Smad3, and Smad4 was upregulated following IUA, whereas Smad7 expression was downregulated. TTR lowers the expression of TGF-β1, Smad2, Smad3, and Smad4 but increases the expression of Smad7 in vivo, indicating that TTR can modulate the expression of the TGF-β1/Smad pathway to mediate fibrosis. In ESCs, the phosphorylation of Smad2 and Smad3 and upregulation of Smad4 were induced by TGF-β1 whereas the expression of Smad7 was inhibited. Administration of TTR reduces the phosphorylation of Smad2 and Smad3, increases Smad4 expression induced by TGF-β1, and promotes the expression of Smad7. TTR modulates the TGF-β1/Smad pathway to alleviate the generation of fibrotic tissue in response to IUA.

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Qishen granule attenuates cardiac fibrosis by regulating TGF-β /Smad3 and GSK-3β pathway

Cited by 78 publications

References 37 publications

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

Qishen granules exerts cardioprotective effects on rats with heart failure via regulating fatty acid and glucose metabolism

Tiaoshen Tongluo Attenuates Fibrosis by Modulating the TGF-β1/Smad Pathway in Endometrial Stromal Cells and a Rat Model of Intrauterine Adhesion

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