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

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.

Autophagy protein 5 enhances the function of rat EPCs and promotes EPCs homing and thrombus recanalization via activating AKT

“…For example, autophagy activation can protect ischemic cell injury [40], extend lifespan in mice [41] and promoting EPC angiogenesis in cancer development [42,43]. Recently, more evidences have suggested that acute increase in autophagy is protective under hypoxia and chronic ischemia conditions, whereas chronic increase in autophagy may lead to apoptosis [44][45][46][47]. Thus, to demonstrate the therapeutic effect of autophagy in DVT, future studies are needed to investigate autophagy kinetics in DVT and its role in thrombus recanalization in vivo.…”

Autophagy in cardiovascular biology

“…Furthermore, rapamycin and its analogs are used clinically to limit VSMC proliferation, such as in drug-eluting coronary artery stents (126,127). Sirolimus from drug-eluting stents induces autophagy in vascular endothelial cells suppressing reendothelialization and revascularization (128).…”

Cell Cycle Regulation of Smooth Muscle Cells—Searching for Inhibitors of Neointima Formation: Is Combretastatin A4 an Alternative to Sirolimus and Paclitaxel?

“…Vincent et al (14) described antiproliferative effects of CA4 on endothelial cells at nontoxic doses of 5 nmol/L and 10 nmol/L. Also, Hayashi et al (15) showed inhibitory effects of sirolimus and paclitaxel on the cell cycle in the low nanomolar range. To ensure comparability, we chose 5 Â 10 À9 mol/L as the concentration in all experiments.…”