Intracellular glutamine level determines vascular smooth muscle cell-derived thrombogenicity

• Published in: Atherosclerosis Vol. 328; pp. 62 - 73
• Main Authors: Koyama, Shohei, Yamashita, Atsushi, Matsuura, Yunosuke, Saito, Yusuke, Maekawa, Kazunari, Gi, Toshihiro, Kitamura, Kazuo, Asada, Yujiro
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.07.2021
• Subjects: Everolimus; Glutamine; Mammalian target of rapamycin (mTOR); Smooth muscle cell; Stent thrombosis; Tissue factor; Smooth muscle cell; Mammalian target of rapamycin (mTOR); Stent thrombosis; Everolimus; Tissue factor; Glutamine
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2021.05.012

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. [Display omitted] •Everolimus-eluting stents (EESs) have low thrombosis rate, with unknown mechanism.•Metabolomics identified EES-implanted arteries as amino acid (glutamine) enriched.•Everolimus downregulates vascular smooth muscle cell-derived thrombogenicity.•Increasing intracellular glutamine level possibly has anti-thrombotic effect.