HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells
HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells
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DOI：
10.1172/jci13131
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发表时间：
2001-08-01
影响因子：
15.9
通讯作者：
Asahara, T
中科院分区：
文献类型：
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作者：
Llevadot, J;Murasawa, S;Asahara, T
内皮祖细胞（EPCs）已从外周血循环单核细胞中分离出来，并显示出与新生血管形成的病灶相结合，与出生后血管发生一致。这些循环EPCs来源于骨髓，在内源性组织缺血或外源性细胞因子刺激下被动员。通过体外骨髓单核细胞趋化实验和体内辛伐他汀处理动物外周血EPC培养实验，我们发现HMG-CoA还原酶抑制剂辛伐他汀增加了EPCs的循环数量。直接证据表明，这种增加的循环EPCs来源于骨髓，并可能促进新生血管的形成，在辛伐他汀治疗的小鼠中得到了证实，这些小鼠移植的骨髓来自转基因供体，这些供体表达β -半乳糖苷酶，受内皮细胞特异性Tie-2启动子的转录调节。通过观察辛伐他汀快速激活EPCs中的Akt蛋白激酶，增强增殖和迁移活性以及细胞存活，提示Akt信号通路在他汀介导EPCs作用中的作用。此外，Akt的显性负过表达导致EPC生物活性的功能性阻断。这些发现表明，通过刺激Akt信号通路增强骨髓源性EPCs的动员是HMG-CoA还原酶抑制剂的一种新功能。
Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in peripheral blood and shown to incorporate into foci of neovascularization, consistent with postnatal vasculogenesis. These circulating EPCs are derived from bone marrow and are mobilized endogenously in response to tissue ischemia or exogenously by cytokine stimulation. We show here, using a chemotaxis assay of bone marrow mononuclear cells in vitro and EPC culture assay of peripheral blood from simvastatin-treated animals in vivo, that the HMG-CoA reductase inhibitor, simvastatin, augments the circulating population of EPCs. Direct evidence that this increased pool of circulating EPCs originates from bone marrow and may enhance neovascularization was demonstrated in simvastatin-treated mice transplanted with bone marrow from transgenic donors expressing beta -galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. The role of Akt signaling in mediating effects of statin on EPCs is suggested by the observation that simvastatin rapidly activates Akt protein kinase in EPCs, enhancing proliferative and migratory activities and cell survival. Furthermore, dominant negative Akt overexpression leads to functional blocking of EPC bioactivity. These findings establish that augmented mobilization of bone marrow-derived EPCs through stimulation of the Akt signaling pathway constitutes a novel function for HMG-CoA reductase inhibitors.