Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rütten H, Fichtlscherer S, Martin H, Zeiher A M
Division of Molecular Cardiology, Department of Medicine IV, University of Frankfurt, Frankfurt, Germany.
J Clin Invest. 2001 Aug;108(3):391-7. doi: 10.1172/JCI13152.
HMG-CoA reductase inhibitors (statins) have been developed as lipid-lowering drugs and are well established to reduce morbidity and mortality from coronary artery disease. Here we demonstrate that statins potently augment endothelial progenitor cell differentiation in mononuclear cells and CD34-positive hematopoietic stem cells isolated from peripheral blood. Moreover, treatment of mice with statins increased c-kit(+)/Sca-1(+)--positive hematopoietic stem cells in the bone marrow and further elevated the number of differentiated endothelial progenitor cells (EPCs). Statins induce EPC differentiation via the PI 3-kinase/Akt (PI3K/Akt) pathway as demonstrated by the inhibitory effect of pharmacological PI3K blockers or overexpression of a dominant negative Akt construct. Similarly, the potent angiogenic growth factor VEGF requires Akt to augment EPC numbers, suggesting an essential role for Akt in regulating hematopoietic progenitor cell differentiation. Given that statins are at least as potent as VEGF in increasing EPC differentiation, augmentation of circulating EPC might importantly contribute to the well-established beneficial effects of statins in patients with coronary artery disease.
HMG-CoA还原酶抑制剂(他汀类药物)已被开发为降脂药物,并且在降低冠状动脉疾病的发病率和死亡率方面已得到充分证实。在此我们证明,他汀类药物能有效增强从外周血分离的单核细胞和CD34阳性造血干细胞中内皮祖细胞的分化。此外,用他汀类药物治疗小鼠可增加骨髓中c-kit(+)/Sca-1(+)阳性造血干细胞,并进一步提高分化的内皮祖细胞(EPC)数量。如药理学PI3K阻滞剂的抑制作用或显性负性Akt构建体的过表达所证明,他汀类药物通过PI 3-激酶/Akt(PI3K/Akt)途径诱导EPC分化。同样,强效血管生成生长因子VEGF需要Akt来增加EPC数量,这表明Akt在调节造血祖细胞分化中起重要作用。鉴于他汀类药物在增加EPC分化方面至少与VEGF一样有效,循环EPC的增加可能对他汀类药物在冠状动脉疾病患者中已确立的有益作用有重要贡献。