Published online before print September 2, 2004, doi: 10.1161/01.ATV.0000144030.39087.3b
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Vascular Biology |
Nitric Oxide–Releasing Aspirin Derivative, NCX 4016, Promotes Reparative Angiogenesis and Prevents Apoptosis and Oxidative Stress in a Mouse Model of Peripheral Ischemia
From the Molecular and Cellular Medicine (C.E.) and Experimental Medicine and Gene Therapy Sections (S.V.L., M.B.S., P.M.), National Institute of Biostructures and Biosystems (INBB), Alghero and Osilo, Italy; the NicOx Research Institute (A.M., P.D.S., E.O.), Milan, Italy; and Internal Medicine (P.M.), University of Sassari, Sassari, Italy.
Correspondence to Dr Paolo Madeddu, National Institute of Biostructures and Biosystems, 07033 Osilo (SS) Italy. E-mail madeddu{at}yahoo.com
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.
We evaluated whether aspirin coupled to an NO-releasing moiety (NCX 4016) exerts vascular protection. Mice given regular chow, NCX 4016, or aspirin underwent operative limb ischemia. Compared with controls, NCX 4016 improved hemodynamic recovery, stimulated angiogenesis, reduced apoptosis and oxidative stress, and increased nitrite levels in circulation and ischemic muscles. This new drug could alleviate the consequences of arterial occlusion.
Key Words: angiogenesis • ischemia • peripheral vascular disease • apoptosis • endothelial cell
This article has been cited by other articles:
 |
|
 |
|
  F. Michel, J.-S. Silvestre, L. Waeckel, S. Corda, T. Verbeuren, J. P. Vilaine, M. Clergue, M. Duriez, and B. I. Levy Thromboxane A2/Prostaglandin H2 Receptor Activation Mediates Angiotensin II-Induced Postischemic Neovascularization Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 488 - 493. [Abstract] [Full Text] [PDF]
|
|