Direct Targeting of the mTOR (Mammalian Target of Rapamycin) Kinase Improves Endothelial Permeability in Drug-Eluting Stents-Brief Report

Arteriosclerosis, Thrombosis, and Vascular Biology
Emanuel HarariAloke V Finn

Abstract

Objective- Drug-eluting stents eluting canonical mTOR (mammalian target of rapamycin) inhibitors are widely used to treat coronary artery disease but accelerate the development of atherosclerosis within the stent (neoatherosclerosis)-a leading cause of late stent failure. We recently showed that canonical mTOR inhibitors bind FKBP12.6 (12.6-kDa FK506-binding protein 12), displace it from calcium release channels, resulting in activation of PKCα (protein kinase Cα) and dissociation of p-120-catenin (p120) from VE-CAD (vascular endothelial cadherin; promoting endothelial barrier dysfunction [EBD]). However, the relevance of these findings to drug-eluting stents remains unknown. Newer generation direct mTOR kinase inhibitors do not bind FKBP12.6 and offer the potential of improving endothelial barrier function while maintaining antirestenotic efficacy, but their actual effects are unknown. We examined the effects of 2 different pharmacological targeting strategies-canonical mTOR inhibitor everolimus and mTOR kinase inhibitors Torin-2-on EBD after stenting. Approach and Results- Using the rabbit model of stenting and a combination of Evans blue dye, confocal and scanning electron microscopy studies, everolimus-eluting stents result...Continue Reading

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Citations

Oct 5, 2018·European Heart Journal. Cardiovascular Pharmacotherapy·Josip A BorovacFilippo Crea
Jul 25, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Jathushan PalasubramaniamKarlheinz Peter
Dec 24, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Hong S LuAlan Daugherty
Apr 28, 2020·Circulation. Cardiovascular Interventions·Hiroyuki JinnouchiAloke V Finn
May 23, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Kimio SatohHiroaki Shimokawa
Jul 28, 2019·Nature Reviews. Cardiology·Sho ToriiAloke V Finn
Mar 26, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Shigeo GodoHiroaki Shimokawa
Jun 25, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Anne CornelissenAloke V Finn
Mar 10, 2020·EuroIntervention : Journal of EuroPCR in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology·Hiroyuki JinnouchiAloke V Finn
Oct 16, 2021·Journal of Cardiovascular Pharmacology·Belay Tesfamariam
Jul 13, 2021·American Journal of Respiratory Cell and Molecular Biology·Xiaolin ChenChongXiu Sun
Dec 4, 2021·Expert Review of Cardiovascular Therapy·Masayuki MoriAloke V Finn

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