Emanueli Costanza, Van Linthout Sophie, Salis Maria Bonaria, Monopoli Angela, Del Soldato Piero, Ongini Ennio, Madeddu Paolo
Molecular and Cellular Medicine, National Institute of Biostructures and Biosystems, Alghero, Italy.
Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2082-7. doi: 10.1161/01.ATV.0000144030.39087.3b. Epub 2004 Sep 2.
Recently, nitric oxide (NO) donors have been developed that mimic the physiological intracellular release of NO. We evaluated whether one of these new compounds, consisting of aspirin coupled to an NO-releasing moiety (NCX 4016), would protect limbs from supervening arterial occlusion.
Mice were assigned to receive regular chow or chow containing NCX 4016 or aspirin (both at 300 mumol/kg body weight, daily) throughout the 3-week experimental period. One week after randomization, they underwent surgical excision of the left femoral artery. Limb blood flow recovery (laser Doppler flowmetry) was accelerated by NCX 4016 as compared with aspirin or vehicle (P<0.05). In controls, histological analysis revealed a 35% increase in the capillary density of ischemic muscles compared with contralateral ones, indicative of spontaneous angiogenesis. Neovascularization was enhanced by NCX 4016 (91%; P<0.05 versus vehicle), but not by aspirin (51%; P=NS versus vehicle). Furthermore, NCX 4016 reduced endothelial cell (EC) apoptosis (4.3+/-1.0 versus 8.7+/-2.0 in aspirin and 12.6+/-3.3 ECs/1000 cap in vehicle; P<0.05 for either comparison) as well as caspase-3 mRNA levels in ischemic muscles ([caspase-3/GAPDH]*100 = 0.09+/-0.04 versus 2.30+/-0.44 in aspirin and 2.30+/-0.32 in vehicle; P<0.01 for either comparison). Nitrite levels and the ratio of reduced to oxidized glutathione were selectively increased in ischemic muscles by NCX 4016. Vascular endothelial growth factor-A expression was reduced by aspirin, with this effect being blunted by NCX 4016.
Pretreatment with the new oral NO-releasing aspirin derivative stimulates reparative angiogenesis and prevents apoptosis and oxidative stress, thereby alleviating the consequences of supervening arterial occlusion.
最近，已研发出可模拟一氧化氮（NO）生理细胞内释放的NO供体。我们评估了一种由阿司匹林与NO释放部分偶联组成的新化合物（NCX 4016）是否能保护肢体免受随后的动脉闭塞影响。
在为期3周的实验期间，将小鼠分为三组，分别给予常规饲料或含NCX 4016或阿司匹林的饲料（均为每日300 μmol/kg体重）。随机分组1周后，对其进行左股动脉手术切除。与阿司匹林或赋形剂相比，NCX 4016可加速肢体血流恢复（激光多普勒血流仪检测）（P<0.05）。在对照组中，组织学分析显示，与对侧相比，缺血肌肉的毛细血管密度增加了35%，表明有自发血管生成。NCX 4016可增强新生血管形成（91%；与赋形剂相比P<0.05），但阿司匹林则无此作用（51%；与赋形剂相比P=无显著性差异）。此外，NCX 4016可减少内皮细胞（EC）凋亡（分别为4.3±1.0、阿司匹林组为8.7±2.0、赋形剂组为12.6±3.3个EC/1000个毛细血管；两种比较P<0.05）以及缺血肌肉中半胱天冬酶-3 mRNA水平（[半胱天冬酶-3/甘油醛-3-磷酸脱氢酶]*100分别为0.09±0.04、阿司匹林组为2.30±0.44、赋形剂组为2.30±0.32；两种比较P<0.01）。NCX 4016可使缺血肌肉中的亚硝酸盐水平以及还原型谷胱甘肽与氧化型谷胱甘肽的比率选择性增加。阿司匹林可降低血管内皮生长因子-A的表达，而NCX 4016可减弱这一作用。
新型口服NO释放阿司匹林衍生物预处理可刺激修复性血管生成，防止细胞凋亡和氧化应激，从而减轻随后动脉闭塞的后果。
