Emanueli, Costanza and Linthout, Sophie Van and Salis, Maria Bonaria and Monopoli, Angela and Del Soldato, Piero and Ongini, Ennio and Madeddu, Paolo Roberto (2004) Nitric oxide-releasing aspirin derivative, NCX 4016, promotes reparative angiogenesis and prevents apoptosis and oxidative stress in a mouse model of peripheral ischemia. Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 24 (11), p. 2082-2087. eISSN 1524-4636. Article.
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Background—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.
Methods and Results—Mice were assigned to receive regular chow or chow containing NCX 4016 or aspirin (both at
300 μmol/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.
Conclusions—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.
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