A rapamycin derivative, biolimus, preferentially activates autophagy in vascular smooth muscle cells

Yerin Kim, Jun Kyu Park, Jun Hyuk Seo, Hyun Seung Ryu, Kyung Seob Lim, Myung Ho Jeong, Dong Hoon Kang, Sang Won Kang

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Although rapamycin is a well-known conformational inhibitor of mTORC1, it is now widely used for treating arterial restenosis. Various rapamycin analogues (rapalogue) have been made for applying to drug-eluting stents. Here we show that two major rapalogues, everolimus and biolimus, exert a differential effect on the mTORC1-mediated signaling pathways in vascular smooth muscle cells. In balloon-injured carotid arteries, both rapalogues strongly inhibit neointimal hyperplasia. Signaling pathway analyses reveal that everolimus exert cytotoxicity by increasing cellular reactive oxygen species and consequently reduce energy metabolism. By contrast, biolimus confers a preferential induction of autophagy by more strongly activating major autophagy regulator, ULK1, in vascular smooth muscle cells than everolimus does. As a consequence, the implantation of biolimus-eluting stent reduces endothelial loss, which in turn reduces inflammation, in porcine coronary arteries. Thus, this study reveals that a chemical derivatization can cause a change among mTORC1-dependent signaling pathways in vascular smooth muscle cells, thereby enabling to elicit a differential efficacy on arterial restenosis.

Original languageEnglish
Article number16551
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - 1 Dec 2018

Bibliographical note

Funding Information:
This study was supported by grants from the National Research Foundation of Korea (NRF-2017M3A9G2077885 and 2012R1A5A1048236). This study was also supported by a grant from the Korean Health Technology R&D Project (H16C0094). D.H.K was a recipient of a Basic Science Research Program Award from the National Research Foundation of Korea (NRF-2014R1A6A3A04058006).

Publisher Copyright:
© 2018, The Author(s).

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