The PPAR-γ agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells
The PPAR-γ agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells
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DOI：
10.1016/j.atherosclerosis.2006.06.026
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发表时间：
2007-05-01
期刊：
影响因子：
5.3
通讯作者：
Laufs, Ulrich
中科院分区：
文献类型：
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作者：
Gensch, Christoph;Clever, Yvonne P.;Laufs, Ulrich
PPAR-γ激动剂(噻唑烷二酮类，TZDS)可独立于胰岛素增敏而改善内皮功能。骨髓来源的血管内皮祖细胞(EPC)有助于新生血管的形成。小鼠每日给予吡格列酮20 mg/kg，连续给药10天。TZD上调血(235+/-60%)和骨髓(166+/-30%)循环中SCA-1/VEGFR-2阳性EPC，培养的脾来源DiLDL/Lectin阳性EPC增加到231+/-21%(n=24)。20d后EPC持续上调。TZD使SDF-1诱导的EPC迁移能力增加246+/-73%，端粒重复序列结合因子2表达增加320+/-50%。体内新生血管增加了两倍(214+/-42%，20天)。一氧化氮合酶抑制剂L-NAME不能抑制TZD诱导的EPC上调。TZD治疗动物的EPC体内凋亡率减少(65+/-2.8%)。在培养的人内皮祖细胞中，吡格列酮预处理可阻止过氧化氢诱导的细胞凋亡。在Wortmannin存在下，TZD对EPC凋亡的抑制作用被取消，但LNMA不能。综上所述，TZD上调内皮祖细胞的数量和功能。吡格列酮以PI3K依赖但非独立的方式抑制小鼠EPC和人EPC的凋亡。TZD减少EPC的凋亡可能是一种潜在的有益于血管疾病患者的机制。(C)2006爱思唯尔爱尔兰有限公司。保留所有权利。
PPAR-gamma agonists (thiazolidinediones, TZDs) may improve endothelial function independently of insulin sensitizing. Bone marrow-derived endothelial progenitor cells (EPC) contribute to neoangiogenesis. Mice were treated with pioglitazone, 20 mg/kg/day for 10 days. Treatment with TZD upregulated circulating Sca-1/VEGFR-2 positive EPC in the blood (235 +/- 60%) and the bone marrow (166 +/- 30%), cultured spleen-derived DiLDL/lectin positive EPC increased to 231 +/- 21% (n = 24 per group). Upregulation of EPC was persistent after 20 days. TZD increased SDF-1-induced migratory capacity per number of EPC by 246 +/- 73% and increased expression of telomere repeat-binding factor 2 by 320 +/- 50%. In vivo neoangiogenesis was increased two-fold (214 +/- 42%, 20 days). The NOS inhibitor L-NAME did not inhibit the TZD-induced upregulation of EPC. EPC from TZD-treated animals showed reduced in vivo apoptosis (65 +/- 2.8% of vehicle). In cultured human EPC, pre-treatment with pioglitazone prevented H2O2-induced apoptosis. Inhibition of EPC apoptosis by TZD was abolished in the presence of wortmannin but not by LNMA. In summary, TZD upregulates both number and functional capacity of endothelial progenitor cells. Pioglitazone prevents apoptosis of EPC in mice as well as in human EPC in a PI3K-dependent but NO-independent manner. Reduction of EPC apoptosis by TZD may be a potentially beneficial mechanism for patients with vascular diseases. (c) 2006 Elsevier Ireland Ltd. All rights reserved.