Abstract 1363: Fluvastatin Accelerates Re-Endothelialization Impaired By Local Sirolimus Treatment.
Backgrounds; Sirolimuseluting stent (SES) has emerged as a promising therapy to prevent in-stent restenosis. However, sirolimus potentially affects re-endothelialization. Recently, endothelial progenitor cells are reported to contribute to re-endothelialization, further, statins are demonstrated to increase these progenitors. Here, we investigated the effects of sirolimus on re-endothelialization after vascular injury and investigated whether fluvastatin has beneficial effect on re-endothelialization after sirolimus treatment.
Methods and Results; Sirolimus (1 ng/ml) inhibited not only the proliferation of human umbilical vein endothelial cells but also the outgrowth of endothelial-like cell from human peripheral blood mononuclear cells in vitro. Wire-mediated vascular injury was induced to both sides of the femoral arteries of bone marrow chimeric mice. Either vehicle or sirolimus was administered locally to the perivascular area of the injured arteries. Sirolimus significantly reduced neointima hyperplasia at 4 weeks (p<0.05). However, re-endothelialization detected by anti-CD31 immunostaining was retarded in the arteries treated with sirolimus (sirolimus vs. vehicle; 7.7±3.4 vs. 55.1±26.1%). Next, we performed the same wire-mediated vascular injury to C57BL/6 mice, following sirolimus or vehicle treatment. Administration of fluvastatin (5mg/kg/day) or vehicle was started from one week before vascular injury to the harvest every day by gavage. In the vehicle group, sirolimus reduced re-endothelialization as determined by the percentage of CD31-positive length in lumen (48.9±9.4 vs. 73.8±5.7%, P<0.01). On the other hand, in the fluvastatin group, there was no significant difference in CD31-positive luminal length between sirolimus treated side and vehicle treated side (73.3±8.4 vs. 79.3±6.3%, P=NS).
Conclusions; Sirolimus affects re-endothelialization through inhibition of proliferation of endothelial cells and differentiation of endothelial progenitor cells. Fluvastatin may have protective effects against retarded re-endothelialization after sirolimus treatment.