Potent inhibitory effect of sirolimus on circulating vascular progenitor cells
Potent inhibitory effect of sirolimus on circulating vascular progenitor cells
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DOI：
10.1161/01.cir.0000155612.47040.17
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发表时间：
2005-02-22
期刊：
影响因子：
37.8
通讯作者：
Nagai, R
中科院分区：
文献类型：
--
作者：
Fukuda, D;Sata, M;Nagai, R
背景-新生内膜增生是支架内再狭窄（ISR）的主要原因。西罗莫司洗脱支架（SES）已成为预防ISR的一种有前景的治疗方法;然而，局部给药西罗莫司（一种免疫抑制剂）预防ISR的确切机制仍不清楚。最近的证据表明，循环祖细胞可能有助于neointimalformation.Methods和结果-单核细胞（MNCs）从健康人类志愿者的外周血中分离。在血小板衍生生长因子-BB和碱性成纤维细胞生长因子存在下，从MNC（1 × 10（6））培养物中长出平滑肌（SM）样细胞，而在血管内皮生长因子存在下获得内皮细胞样细胞。西罗莫司有效抑制SM样细胞生长。在低至0.1 ng/mL的浓度下，SM样细胞的数量显著减少（对照的15.9 +/- 5.8%，P < 0.001）。西罗莫司对来源于单核细胞的内皮细胞样细胞也有抑制作用.在骨髓嵌合体小鼠的股动脉中诱导导丝介导的血管损伤。在损伤动脉的血管周围区域局部给予溶媒或西罗莫司。西罗莫司在4周时显著减少了新生内膜增生（内膜/中膜比2.0 +/-0.3与1.0 +/-0.2，P < 0.05），病变中骨髓来源的SM样细胞和造血细胞的数量减少。西罗莫司治疗的动脉再内皮化延迟。结论西罗莫司对循环平滑肌祖细胞的有效抑制作用可能介导SES的临床疗效，至少部分。西罗莫司可能影响支架植入后的再内皮化。
Background - Neointimal hyperplasia is the major cause of in-stent restenosis (ISR). The sirolimus-eluting stent (SES) has emerged as a promising therapy to prevent ISR; however, the exact mechanism by which locally delivered sirolimus, an immunosuppressive agent, prevents ISR remains unknown. Recent evidence suggests that circulating progenitor cells may contribute to neointimal formation.Methods and Results - Mononuclear cells (MNCs) were isolated from peripheral blood of healthy human volunteers. Smooth muscle (SM)-like cells outgrew from the culture of MNCs (1 x 10(6)) in the presence of platelet-derived growth factor-BB and basic fibroblast growth factor, whereas endothelial cell - like cells were obtained in the presence of vascular endothelial growth factor. Sirolimus potently inhibited SM-like cell outgrowth. The number of SM-like cells was significantly reduced at a concentration as low as 0.1 ng/mL (15.9 +/- 5.8% of control, P < 0.001). Sirolimus also exerted an inhibitory effect on endothelial cell - like cells that originated from MNCs. Wire-mediated vascular injury was induced in 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 (intima/media ratio 2.0 +/- 0.3 versus 1.0 +/- 0.2, P < 0.05) with a decreased number of bone marrow - derived SM-like cells and hematopoietic cells in the lesion. Reendothelialization was retarded in the arteries treated with sirolimus.Conclusions - The potent inhibitory effects of sirolimus on circulating smooth muscle progenitor cells may mediate the clinical efficacy of SES, at least in part. Sirolimus potentially may affect reendothelialization after stent implantation.