Xianglan Liu1,2,3, Ruoxi Zhang3,4, Guosheng Fu1,2, Yong Sun3,4, Jian Wu3,4, Maomao Zhang3,4, Jinwei Tian3,4, Xia Gu3,4, Yang Zheng3,4, Chengming Shi3,4, Jingbo Hou3,4, Bo Yu5,6,7. 1. Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Qingchundong Road No. 3, Jianggan District, Hangzhou, China. 2. Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China. 3. Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China. 4. Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Xuefu Road No. 246, Nangang District, Harbin, China. 5. Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China. dryu_hmu@163.com. 6. Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Xuefu Road No. 246, Nangang District, Harbin, China. dryu_hmu@163.com. 7. Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. dryu_hmu@163.com.
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.
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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