Published online before print October 8, 2009

This Article Full Text (Rapid PDF) Supplementl Material All Versions of this Article: ajpath.2009.090152v1 175/5/2226    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Hayashi, S.-i. Articles by Nakashima, S. PubMed PubMed Citation Articles by Hayashi, S.-i. Articles by Nakashima, S.

Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.090152

Accepted for publication July 9, 2009.

Article

The Stent-Eluting Drugs Sirolimus and Paclitaxel Suppress Healing of the Endothelium by Induction of Autophagy

Shin-ichiro Hayashi^*@, Akitsugu Yamamoto, Fukka You^*, Kentaro Yamashita^*, Yuka Ikegame^*, Masahiro Tawada^*, Tamotsu Yoshimori, Shigeomi Shimizu^¶, and Shigeru Nakashima^*

From the Department of Cell Signaling,* Gifu University Graduate School of Medicine, Gifu, Japan; the Nagahama Institute of Bioscience and Technology, Shiga, Japan; the Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and the Department of Pathological Cell Biology,^¶ Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: Shin559182{at}aol.com.

	Abstract

Clinical studies have indicated that the stent-eluting drugs sirolimus and paclitaxel impact restenosis; however, it is still elusive how these drugs affect the vascular endothelium at the molecular and cellular levels. The purpose of this study was to determine whether sirolimus and paclitaxel induce molecular and cellular alterations in the vascular endothelium. Endothelial regrowth was assessed in human aortic endothelial cells and rat aortic endothelium. Molecular and cellular alterations were analyzed in human aortic endothelial cells by Western blot analysis, transmission electron microscopy, and immunofluorescence staining. Green fluorescent protein-LC3 mice were used to analyze autophagic endothelium. Here, we show that sirolimus and paclitaxel differentially induce self-digesting autophagy in vascular endothelial cells with changes in expression of LC3B, p53, and Bcl-2, considerably suppressing re-endothelialization and revascularization. These results suggest that phenotypic alteration in the endothelium by sirolimus or paclitaxel might affect the rates of late stent thrombosis, myocardial infarction, and mortality.