Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Qingchundong Road No. 3, Jianggan District, Hangzhou, China.
Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China.
Cardiovasc Drugs Ther. 2021 Oct;35(5):915-925. doi: 10.1007/s10557-020-07121-7. Epub 2021 Jan 4.
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.
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).
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.
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.
药物洗脱支架释放的抗增殖药物会延迟细胞覆盖和血管愈合，从而增加晚期支架血栓形成的风险。我们评估了全身甲氨蝶呤（MTX）对体内和体外细胞覆盖、血管愈合和炎症激活的潜在影响。
我们在兔支架模型中在右颈总动脉应用 MTX，通过连续光学相干断层扫描（OCT）分析来确定其对细胞覆盖和炎症激活的影响，并阐明 MTX 在人脐静脉内皮细胞（HUVEC）中的分子机制。
低剂量 MTX 促进了细胞覆盖和血管愈合的发展，这与支架置入 4 周时的无覆盖支架（%）和任何无覆盖支架的横截面（%）较少有关。MTX 组在支架置入 12 周时也表现出较低的异质性、微血管和每支架低信号强度层的发生率，表明新生内膜不稳定。在体外，低剂量 MTX 通过靶向磷脂酰肌醇 3-激酶（PI3K）/AKT 信号通路强烈抑制 HUVEC 凋亡，促进增殖并抑制炎症激活。
低剂量 MTX 可能是通过抑制支架植入后炎症反应和新生内膜的稳定性，促进早期细胞覆盖的关键手段。
