Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/β-catenin signalling pathway
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Zhu, Mengmeng
Ma, Jialing
Liu, Zhenghong
Zhang, Zhidan
Chen, Meijie
Zhao, Yaping
Li, Huaxin
Wang, Shengnan
Wei, Xiaoning
Zhang, Wenwen
Yang, Xiaoxiao
Little, Peter J
Kamato, Danielle
Hu, Hao
et al.
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Abstract
Introduction Vascular calcification, a devastating vascular complication accompanying atherosclerotic cardiovascular disease and chronic kidney disease, increases the incidence of adverse cardiovascular events and compromises the efficacy of vascular interventions. However, effective therapeutic drugs and treatments to delay or prevent vascular calcification are lacking.
Objectives This study was designed to test therapeutic effects and mechanism of Moscatilin from Dendrobium huoshanense (an eminent traditional Chinese medicine) in suppressing vascular calcification in vitro, ex vivo and in vivo.
Methods Male C57BL/6J mice (25-week-old) were subjected to nicotine and vitamin D3 (VD3) treatment to induce vascular calcification. In vitro, we established the cellular model of osteogenesis of human aortic smooth muscle cells (HASMCs) under phosphate conditions.
Results By utilizing an in-house drug screening protocol, we identified Moscatilin as a new naturally-occurring chemical entity to reduce HASMC calcium accumulation. The protective effects of Moscatilin against vascular calcification were verified in cultured HASMCs. Unbiased transcriptional profiling analysis and cellular thermal shift assay suggested that Moscatilin suppresses vascular calcification via binding to interleukin 13 receptor subunit A2 (IL13RA2) and augmenting its expression. Furthermore, IL13RA2 was reduced during HASMC osteogenesis, thus promoting the secretion of inflammatory factors via STAT3. We further validated the participation of Moscatilin-inhibited vascular calcification by the classical WNT/β-catenin pathway, among which WNT3 played a key role in this process. Moscatilin mitigated the crosstalk between WNT3/β -catenin and IL13RA2/STAT3 to reduce osteogenic differentiation of HASMCs.
Conclusion This study supports the potential of Moscatilin as a new naturally-occurring candidate drug for treating vascular calcification via regulating the IL13RA2/STAT3 and WNT3/β -catenin signalling pathways.
Abbreviations ALPLalkaline phosphataseBMP2bone morphogenetic protein 2OPNosteopontinRUNX2runt related transcription factor 2HASMCshuman aortic smooth muscle cellsWNT3WNT family member 3IL13RA2interleukin 13 receptor subunit alpha 2STAT3signal transducer and activator of transcription 3VD3vitamin D3
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Journal of Advanced Research
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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International (CC BY-NC-ND 4.0) License, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
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This publication has been entered in Griffith Research Online as an advanced online version.
Copyright permissions for this publication were identified from the publisher's website at https://doi.org/10.1016/j.jare.2024.02.020
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Primary health care
IL13RΑ2
Moscatilin
STAT3
Vascular calcification
WNT3
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Zhang, T; Zhu, M; Ma, J; Liu, Z; Zhang, Z; Chen, M; Zhao, Y; Li, H; Wang, S; Wei, X; Zhang, W; Yang, X; Little, PJ; Kamato, D; Hu, H; et al., Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/β-catenin signalling pathway, Journal of Advanced Research, 2024