The stent-eluting drugs sirolimus and paclitaxel suppress healing of the endothelium by induction of autophagy.
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.
Hayashi
Shin-ichiro
S
Department of Cell Signaling, Gifu University Graduate School of Medicine, Japan. Shin559182@aol.com
Yamamoto
Akitsugu
A
You
Fukka
F
Yamashita
Kentaro
K
Ikegame
Yuka
Y
Tawada
Masahiro
M
Yoshimori
Tamotsu
T
Shimizu
Shigeomi
S
Nakashima
Shigeru
S
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001011:Aorta / Q000033:anatomy & histology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D054855:Drug-Eluting Stents; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*
D000972:Antineoplastic Agents, Phytogenic; D008869:Microtubule-Associated Proteins; D017239:Paclitaxel; D011993:Recombinant Fusion Proteins; D020123:Sirolimus; D050257:Tubulin Modulators; C526109:Anxa3 protein, rat