Exogenous testosterone alleviates cardiac fibrosis and apoptosis via Gas6/Axl pathway in the senescent mice

Chen, Fang‐Fang; Song, Fang-qiang; Chen, Yanqing; Wang, Zhi-Hao; Li, Yihui; Liu, Minghao; Wang, Yongdong; Song, Ming; Zhang, Wei; Zhao, Jing; Zhong, Ming

doi:10.1016/j.exger.2019.01.029

Cited by 14 publications

(13 citation statements)

References 46 publications

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“…However, our results show that there was no change in Axl protein and mRNA expression, which was inconsistent with a previous study (Chen et al. 2019 ). The TAM receptor family includes Tyro3, Axl and MerTK.…”

Section: Discussioncontrasting

confidence: 99%

“…A previous study demonstrated the roles of Gas6/Axl in regulating multiple cellular functions (Chen et al. 2019 ). A recent study suggested that Gas6/Axl played a crucial role in vascular calcification (Son et al.…”

Section: Discussionmentioning

confidence: 96%

“… 2019 ) and may also be involved in treatment-induced downregulation of collagen synthesis in VSMCs and ageing heart tissue (Chen et al. 2016 ; 2019 ). Moreover, previous studies revealed that Rb1 activated Gas6 transcription at the specific ARE site in the promoter region (Son et al.…”

Section: Discussionmentioning

confidence: 99%

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Ginsenoside Rb1 attenuates age-associated vascular impairment by modulating the Gas6 pathway

Shi

Wang

et al. 2021

Pharmaceutical Biology

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Context Ginsenoside Rb1 (Rb1) exerts many beneficial effects and protects against cardiovascular disease. Objective To investigate whether Rb1 could attenuate age-related vascular impairment and identify the mechanism. Materials and methods Female C57BL/6J mice aged 2 and 18 months, randomly assigned to Young, Young + 20 mg/kg Rb1, Old + vehicle, Old + 10 mg/kg Rb1 and Old + 20 mg/kg Rb1 groups, were daily intraperitoneal injected with vehicle or Rb1 for 3 months. The thoracic aorta segments were used to inspect the endothelium-dependent vasorelaxation. Left thoracic aorta tissues were collected for histological or molecular expression analyses, including ageing-related proteins, markers relevant to calcification and fibrosis, and expression of Gas6/Axl. Results We found that in Old + vehicle group, the expression of senescence proteins and cellular adhesion molecules were significantly increased, with worse endothelium-dependent thoracic aorta relaxation (58.35% ± 2.50%) than in Young group (88.84% ± 1.20%). However, Rb1 treatment significantly decreased the expression levels of these proteins and preserved endothelium-dependent relaxation in aged mice. Moreover, Rb1 treatment also reduced calcium deposition, collagen deposition, and the protein expression levels of collagen I and collagen III in aged mice. Furthermore, we found that the downregulation of Gas6 protein expression by 41.72% and mRNA expression by 52.73% in aged mice compared with young mice was abrogated by Rb1 treatment. But there was no significant difference on Axl expression among the groups. Conclusions Our study confirms that Rb1 could ameliorate vascular injury, suggesting that Rb1 might be a potential anti-ageing related vascular impairment agent.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 96%

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Ginsenoside Rb1 attenuates age-associated vascular impairment by modulating the Gas6 pathway

Shi

Wang

et al. 2021

Pharmaceutical Biology

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“…Endothelial Notch1 overexpression results in LSEC dedifferentiation and accelerates liver fibrogenesis through eNOS-sGC signaling, and it alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration (Duan et al, 2018). DLL4, a ligand of Notch signaling, is up-regulated in the LSECs of fibrotic liver of patients and of mice treated with CCl 4 , consistent with LSEC capillarization involving endothelin-1 (Chen et al, 2019a). Notch signaling is an attractive target for treating liver fibrosis; so far, Wnt/β-catenin signaling, miR-30c, liver fibrosis-associated lncRNA1 have been found to influence such signaling (Zhang et al, 2017;So et al, 2018;Gu et al, 2021).…”

Section: Notch Signalingmentioning

confidence: 68%

Novel Therapeutic Targets in Liver Fibrosis

Zhang

Liu

et al. 2021

Front. Mol. Biosci.

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Liver fibrosis is end-stage liver disease that can be rescued. If irritation continues due to viral infection, schistosomiasis and alcoholism, liver fibrosis can progress to liver cirrhosis and even cancer. The US Food and Drug Administration has not approved any drugs that act directly against liver fibrosis. The only treatments currently available are drugs that eliminate pathogenic factors, which show poor efficacy; and liver transplantation, which is expensive. This highlights the importance of clarifying the mechanism of liver fibrosis and searching for new treatments against it. This review summarizes how parenchymal, nonparenchymal cells, inflammatory cells and various processes (liver fibrosis, hepatic stellate cell activation, cell death and proliferation, deposition of extracellular matrix, cell metabolism, inflammation and epigenetics) contribute to liver fibrosis. We highlight discoveries of novel therapeutic targets, which may provide new insights into potential treatments for liver fibrosis.

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“…Previous studies have found that activated TAM receptors can significantly upregulate the expression of SOCS3 ( Rothlin et al, 2007 ). Moreover, activation of Gas6/Axl signaling pathway can alleviate cardiac fibrosis and apoptosis ( Chen et al, 2019 ). Due to Axl receptor is highly expressed in the heart ( Batlle et al, 2014 ), we speculated that bilirubin inducing the expression of SOCS3 may by activating the Axl receptor in heart.…”

Section: Discussionmentioning

confidence: 99%

Bilirubin Improves Gap Junction to Alleviate Doxorubicin-Induced Cardiotoxicity by Regulating AMPK-Axl-SOCS3-Cx43 Axis

et al. 2022

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Doxorubicin induces severe cardiotoxicity, accompanied by the high level of bilirubin in the blood. The conventional wisdom is that bilirubin is considered as a marker of liver damage. By contrast, here we aim to explore the potential protective effect of bilirubin on doxorubicin-induced cardiotoxicity, and investigate the mechanism for drug development. Doxorubicin was used to establish cardiotoxicity model in vitro and in vivo. The electrocardiogram (ECG), echocardiography and molecular biological methods were used to detect the effects of bilirubin on doxorubicin-induced cardiotoxicity. Consecutive intraperitoneal injection of bilirubin for 7 days significantly attenuated doxorubicin-induced arrhythmia, prolonged survival time and reduced the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) and α-hydroxybutyrate dehydrogenase (α-HBDH) in mice. Bilirubin also markedly inhibited doxorubicin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and connexin 43 (Cx43), and improved gap junction function in vitro and in vivo. In addition, bilirubin activated adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and induced suppressor of cytokine signaling 3 (SOCS3) expression, which was abolished by Axl inhibition. Moreover, pretreatment with AMPK agonist or AMPK inhibitor could mimic or abolish the cardioprotective effect of bilirubin on H9C2 cells in vitro, respectively. Altogether, bilirubin upregulates gap junctions’ function to protect against doxorubicin-induced cardiotoxicity by activating AMPK-Axl-SOCS3 signaling axis. We enrich the physiological function of bilirubin, and provide theoretical support for drug development.

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Exogenous testosterone alleviates cardiac fibrosis and apoptosis via Gas6/Axl pathway in the senescent mice

Cited by 14 publications

References 46 publications

Ginsenoside Rb1 attenuates age-associated vascular impairment by modulating the Gas6 pathway

Ginsenoside Rb1 attenuates age-associated vascular impairment by modulating the Gas6 pathway

Novel Therapeutic Targets in Liver Fibrosis

Bilirubin Improves Gap Junction to Alleviate Doxorubicin-Induced Cardiotoxicity by Regulating AMPK-Axl-SOCS3-Cx43 Axis

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