Passacquale Gabriella, Desideri Giovambattista, Croce Giuseppe, Murgo Simona, Mancarelli Maria Michela, Zazzeroni Francesca, Alesse Edoardo, Ferri Claudio
Department of Internal Medicine and Public Health, University of L'Aquila, L'Aquila, Italy.
J Hypertens. 2008 Apr;26(4):737-46. doi: 10.1097/HJH.0b013e3282f4d1bd.
Migratory ability of resident endothelial cells and their circulating progenitors, that is endothelial progenitor cells (EPCs), represent a crucial event in vascular repairing processes. Although oxidants are known to counteract the migratory ability of resident endothelial cells, their possible role in modulating EPC motility is unknown. EPCs exhibit stronger resistance to oxidants than mature endothelial cells mainly because of higher expression of manganese (Mn) superoxide dismutase (SOD). As nifedipine is a dihydropyridine calcium antagonist known to enhance MnSOD expression in mature endothelial cells, we investigated the effects of nifedipine on MnSOD expression and motility in EPCs.
EPCs were isolated from peripheral blood of healthy donors and cultured in fibronectin-coated flasks. Nifedipine improved both motility of cultured EPCs (+55% vs. control, P = 0.007) and their adhesion to tumor necrosis factor-alpha-activated mature endothelial cells (+33% vs. control, P = 0.03). Reduction of EPC dichlorofluorescein content (-32% vs. control, P = 0.009) and a parallel increase in nitrite plus nitrate concentration in EPC supernatants (+25% vs. control, P = 0.009) were also observed. The study of SOD showed a nifedipine-dependent upregulation of MnSOD in a time-dependent and dose-dependent manner. MnSOD expression blockade by RNA interference abolished nifedipine effect on EPC motility. Although nifedipine also increased vascular endothelial growth factor (VEGF) release from EPCs, its effect on EPC motility was unaffected by an anti-VEGF antibody.
Nifedipine improves EPC motility due to MnSOD upregulation. The capability of this dihydropyridine calcium antagonist to reduce cardiovascular events might also be related to improved EPC function.
驻留内皮细胞及其循环祖细胞（即内皮祖细胞，EPCs）的迁移能力是血管修复过程中的关键事件。虽然已知氧化剂会抵消驻留内皮细胞的迁移能力，但其在调节EPCs运动性方面的可能作用尚不清楚。EPCs对氧化剂的抵抗力比成熟内皮细胞更强，主要是因为锰（Mn）超氧化物歧化酶（SOD）的表达更高。由于硝苯地平是一种二氢吡啶类钙拮抗剂，已知可增强成熟内皮细胞中MnSOD的表达，我们研究了硝苯地平对EPCs中MnSOD表达和运动性的影响。
从健康供体的外周血中分离出EPCs，并在纤连蛋白包被的培养瓶中培养。硝苯地平改善了培养的EPCs的运动性（与对照组相比增加55%，P = 0.007）及其与肿瘤坏死因子-α激活的成熟内皮细胞的粘附（与对照组相比增加33%，P = 0.03）。还观察到EPCs二氯荧光素含量降低（与对照组相比降低32%，P = 0.009），同时EPCs上清液中亚硝酸盐加硝酸盐浓度平行增加（与对照组相比增加25%，P = 0.009）。对SOD的研究表明，硝苯地平以时间和剂量依赖性方式上调MnSOD。RNA干扰阻断MnSOD表达消除了硝苯地平对EPC运动性的影响。虽然硝苯地平也增加了EPCs中血管内皮生长因子（VEGF）的释放，但其对EPC运动性的影响不受抗VEGF抗体的影响。
硝苯地平通过上调MnSOD改善EPC运动性。这种二氢吡啶类钙拮抗剂降低心血管事件的能力也可能与改善EPC功能有关。
