不同药物对内皮前体细胞的动员

目的研究不同剂量的阿托伐他汀及雌激素、重组人粒细胞集落刺激因子（G-CSF）在不同时相对内皮前体细胞（EPCs）的动员作用,以寻求合适药物、用药剂量及最佳作用时间。方法将48只体重为2～2．5kg的雄性新西兰兔随机分为六组：每组8只,即对照组,阿托伐他汀2．5mg组、5mg组、10nag组,雌激素组,G．CSF组。用药后1、2．3、4周测量外周血EPC含量。启用流式细胞仪计数PE-CD34／FITC-CDl33双阳性细胞为EPC;荧光显微镜鉴定FITC-UEA-1／Dil-acLDL双染色阳性细胞为EPC。用药第3周测血清一氧化氮（NO）、血脂。结果用药1、2．3、4周六组外周血EPCs的曲线：对照组为一低水平基线;G-CSF组持续稳定于高水平;阿托伐他汀5mg组、雌激素组、阿托伐他汀2．5mg组（按作用从大到小排列）为锯齿样曲线,第2周最低,第3周最高,第4周较第3周低;阿托伐他汀10mg组与对照组接近,仅第4周增高（P〈0．05）。从用药1周开始到第4周,阿托伐他汀5mg组与G-CSF组对EPCs有持续动员作用,第3周该两组效果最佳,约为第1周的3倍,是对照组的近20倍;阿托伐他汀2．5mg组在第3、4周有作用,P〈0．05,P〈0．01;雌激素组EPCs在第3、4周有作用,第3周尤明显,此时雌激素与G-CSF组作用相当,但不及阿托伐他汀5mg组明显。P〈0．01。第4周,五个用药组EPCs均较对照组高,其中G-CSF组最高,另外四组次之,且这四组间无统计学差异。第3周检测血清NO,与对照组相比,阿托伐他汀5mg组和雌激素组NO增高,阿托伐他汀10mg组降低,P〈0．01。各组血脂均在正常范围内。结论阿托伐他汀、雌激素、G-CSF对EPCs均有动员作用,且不同药物组对EPCs的动员效果与时间有交互作用。动员效果为：G-CSF组〉阿托伐他汀5mg组〉雌激素组〉阿托伐他汀2．5mg组〉阿托伐他汀10mg组。阿托伐他汀5mg组在第3周效果最佳。G-CSF对EPCs动员稳定于高水平。阿托伐他汀和雌激素对EPCs的动员可能与NO有关。

Time course of G-CSF, estrogen and various doses of atorvastatin on endothelial progenitor cells mobilization

OBJECTIVE: To evaluate the time course of granulocyto-colony-stimulating-factor (G-CSF), estrogen and various doses of atorvastatin on endothelial progenitor cells (EPCs) mobilization. METHOD: A total of 48 male New Zealand White rabbits were treated with placebo, estrogen (0.25 mg.k(-1).d(-1)), Atorvastatin (2.5, 5, or 10 mg) and G-CSF (50 microg/rabbit/d), respectively. Peripheral EPCs number was surveyed weekly for 4 weeks by FACS analysis (double-positive for PE-CD34/FITC-CD133) and under fluorescent microscope (double-positive for FITC-UEA-1/Dil-acLDL). Serum nitric oxide (NO) and lipids were also measured at the third week. RESULTS: Peripheral EPCs was significantly increased in G-CSF treated animals and remained constant for 4 weeks compared to placebo treated animals. Atorvastatin increased peripheral EPCs dose-dependently from 2.5 to 5 mg and peaked at the third week while peripheral EPCs number was not affected by 10 mg.k(-1).d(-1) atorvastatin during the first 3 weeks and was significantly higher only in the fourth week compared to placebo group. Estrogen also significantly increased peripheral EPCs at the third and fourth week compared to placebo group. At the third week, serum NO was similar in G-CSF group, significantly higher in atorvastatin 5 mg.k(-1).d(-1) and estrogen groups while significantly lower in atorvastatin 10 mg.k(-1).d(-1) group compared to placebo group. Serum lipids were similar among various groups. CONCLUSION: Atorvastatin, estrogen and G-CSF could mobilize EPCs. The mobilization efficacy is as follows: G-CSF > atorvastatin 5 mg.k(-1).d(-1) > estrogen > atorvastatin 2.5 mg.k(-1).d(-1) > atorvastatin 10 mg.k(-1).d(-1). NO might partly contribute to the mobilizing effect of estrogen and atorvastatin.