Koyama Shohei, Yamashita Atsushi, Matsuura Yunosuke, Saito Yusuke, Maekawa Kazunari, Gi Toshihiro, Kitamura Kazuo, Asada Yujiro
Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan; Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan.
Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan.
Atherosclerosis. 2021 Jul;328:62-73. doi: 10.1016/j.atherosclerosis.2021.05.012. Epub 2021 May 26.
The everolimus-eluting stent (EES), one of the effective stents for in-stent restenosis (ISR), has a lower incidence of stent thrombosis; however, the underlying mechanism remains unknown. This study aimed to identify the effects of everolimus on vascular metabolism and thrombogenicity and examine their mechanistic link.
EESs and bare-metal stents were implanted in rabbit iliac arteries with smooth muscle cell (SMC)-rich neointima induced by endothelial denudation. Four weeks after stent implantation, the stented arteries were examined for histological analysis and metabolomics. Additionally, everolimus effects in coronary artery SMCs metabolism, tissue factor (TF) expression, and procoagulant activity were assessed in vitro.
EES-implanted arteries showed decreased neointima formation, less SMCs infiltration, and reduced TF expression. Concomitantly, they were metabolically characterized by increased levels of metabolites in amino acids, such as glutamine. Similarly, everolimus increased intracellular glutamine levels, decreased TF expression, and reduced procoagulant activity in SMCs in vitro. On the contrary, exogenous glutamine administration also increased intracellular glutamine level, decreased TF expression, and reduced procoagulant activity despite enhanced mammalian target of rapamycin (mTOR) activity.
Intracellular glutamine level is likely to determine vascular SMC-related thrombogenicity regardless of mTOR pathway activity. Therefore, increased intracellular glutamine level might contribute partially to the beneficial effect of EES use on stent thrombosis.
依维莫司洗脱支架（EES）是治疗支架内再狭窄（ISR）的有效支架之一，其支架血栓形成发生率较低；然而，其潜在机制仍不清楚。本研究旨在确定依维莫司对血管代谢和血栓形成性的影响，并探讨其机制联系。
将EES和裸金属支架植入经内皮剥脱诱导形成富含平滑肌细胞（SMC）新生内膜的兔髂动脉。支架植入4周后，对置入支架的动脉进行组织学分析和代谢组学研究。此外，在体外评估依维莫司对冠状动脉SMC代谢、组织因子（TF）表达和促凝活性的影响。
植入EES的动脉显示新生内膜形成减少、SMC浸润减少以及TF表达降低。同时，其代谢特征为氨基酸（如谷氨酰胺）代谢物水平升高。同样，依维莫司在体外可提高SMC内谷氨酰胺水平、降低TF表达并降低促凝活性。相反，外源性给予谷氨酰胺尽管增强了雷帕霉素靶蛋白（mTOR）活性，但也提高了细胞内谷氨酰胺水平、降低了TF表达并降低了促凝活性。
无论mTOR途径活性如何，细胞内谷氨酰胺水平可能决定血管SMC相关的血栓形成性。因此，细胞内谷氨酰胺水平升高可能部分促成了使用EES对支架血栓形成的有益作用。
