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Methotrexate Therapy Promotes Cell Coverage and Stability in in-Stent Neointima

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Abstract

Purpose

Anti-proliferative drugs released from drug-eluting stents delay cell coverage and vascular healing, which increases the risk of late stent thrombosis. We assessed the potential effects of systemic methotrexate (MTX) on cell coverage, vascular healing and inflammation activation in vivo and in vitro.

Methods

We applied MTX in the right common carotid artery in a rabbit stenting model to determine the impact on cell coverage and inflammation activation using a serial optical coherence tomography (OCT) analysis and elucidated the molecular mechanism of MTX in human umbilical vein endothelial cells (HUVECs).

Results

Low-dose MTX promoted the development of cell coverage and vascular healing, which was associated with fewer uncovered struts (%) and cross-sections with any uncovered struts (%) at 4 weeks of stenting. The MTX group also exhibited lower rates of heterogeneity, microvessels and per-strut low-signal-intensity layers, indicating neointimal instability at 12 weeks of stenting. In vitro, low-dose MTX strongly inhibited HUVEC apoptosis, promoted proliferation and inhibited inflammatory activation by targeting the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway.

Conclusion

Low-dose MTX may be a key means of promoting early cell coverage via the inhibition of the inflammatory response and stability of neointima by targeting inflammatory pathways after stent implantation.

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Funding

This study was funded by the National Key R&D Program of China (Grant No. 2016YFC1301100), the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, Heilongjiang Province, China (Grant Nos. KF201811 and KF201916), the General Undergraduate Colleges and Universities Young Innovative Talents Training Plan, Heilongjiang Province, China (Grant No. UNPYSCT-2018075), and the Zhejiang Provincial Natural Science Foundation of China (Grant No. LQ21H020006).

Author information

Authors and Affiliations

  1. Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Qingchundong Road No. 3, Jianggan District, Hangzhou, China

    Xianglan Liu & Guosheng Fu

  2. Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China

    Xianglan Liu & Guosheng Fu

  3. Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China

    Xianglan Liu, Ruoxi Zhang, Yong Sun, Jian Wu, Maomao Zhang, Jinwei Tian, Xia Gu, Yang Zheng, Chengming Shi, Jingbo Hou & Bo Yu

  4. Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Xuefu Road No. 246, Nangang District, Harbin, China

    Ruoxi Zhang, Yong Sun, Jian Wu, Maomao Zhang, Jinwei Tian, Xia Gu, Yang Zheng, Chengming Shi, Jingbo Hou & Bo Yu

  5. Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150086, China

    Bo Yu

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  1. Xianglan Liu
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Contributions

Y.B., H.J., Z.R. and L.X. designed the study. L.X. and Z.R. performed literature search, analysed and interpreted the data, and drafted the manuscript. F.G., S.Y. and W.J. contributed to the data collection. Z.M., T.J. and G.X. contributed to the data analysis and interpretation. Z.Y. and S.C. contributed to the literature search and data interpretation. All co-authors edited and reviewed the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Bo Yu.

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Conflict of interest

The authors have no conflicts of interest to declare.

Ethics approval

The Hospital Scientific Affairs Committee on Animal Research and Ethics approved the study protocol, and the methods were performed in accordance with the ARRIVE guidelines. All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All rabbits were obtained from the animal centre of Harbin Medical University.

Consent to participate

This article does not contain any studies involving human participants performed by any of the authors.

Additional information

Xianglan Liu and Ruoxi Zhang have equally contributed for this article.

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Liu, X., Zhang, R., Fu, G. et al. Methotrexate Therapy Promotes Cell Coverage and Stability in in-Stent Neointima. Cardiovasc Drugs Ther 35, 915–925 (2021). https://doi.org/10.1007/s10557-020-07121-7

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