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Originally published online as doi:10.2353/ajpath.2009.090152 on October 8, 2009

Published online before print October 8, 2009
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(American Journal of Pathology. 2009;175:2226-2234.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090152

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

Shin-ichiro Hayashi*, Akitsugu Yamamoto{dagger}, Fukka You*, Kentaro Yamashita*, Yuka Ikegame*, Masahiro Tawada*, Tamotsu Yoshimori{ddagger}, Shigeomi Shimizu§ and Shigeru Nakashima*

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

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.






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Copyright © 2009 by the American Society for Investigative Pathology.