Nitric Oxide–Releasing Aspirin Derivative, NCX 4016, Promotes Reparative Angiogenesis and Prevents Apoptosis and Oxidative Stress in a Mouse Model of Peripheral Ischemia

Abstract

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 mol/kg body weight, daily) throughout the 3-week experimental period. One week after randomization, they underwent surgical excision of the left femoral artery. Key Words: angiogenesis Ⅲ ischemia Ⅲ peripheral vascular disease Ⅲ apoptosis Ⅲ endothelial cell A ngiogenesis is essential for the repair of wounds and tissues damaged by ischemia. The regenerative process is tightly regulated by master angiogenic factors, cytokines, and the downstream mediator nitric oxide (NO). 1,2 In addition, modulators of vascular growth, such as COX-2-generated prostanoids, contribute to the process by stabilizing the hypoxia-inducible factor 3 and by stimulating the expression of vascular endothelial growth factor (VEGF). 4 The physiological overlapping of NO and prostaglandins implies that they can compensate reciprocally in maintaining vascular endothelium integrity. Conversely, postischemic healing could be severely compromised under conditions in which both systems are functionally impaired. 5,6 For instance, elderly patients taking nonsteroidal anti-inflammatory drugs may fail to mount an efficient reparative angiogenesis because of the concomitant aging-related loss of NO biologic activity and/or biosynthesis. In a therapeutic perspective, delivery of NO could represent a way for counterbalancing the endogenous deficit and simultaneously surrogate the lack of angiogenic prostaglandins.Among the many attempts made to improve the profile of nonsteroidal anti-inflammatory drugs, the approach based on grafting an NO-releasing moiety has provided results of therapeutic interest. 7,8 A modified version of aspirin that releases NO surpasses its parent compound in terms of improved cardiovascular protection and reduced gastrointestinal side effects (see Wallace and Del Soldato for review). 7 NCX 4016, 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester, consists of acetylsalicylic acid, to which a nitrate group has been covalently linked through a spacer. In contrast to conventional 19 and inflammation 20 (via inhibition of cytokine release and downregulation of iNOS and tissue factor expression), 21,22 and modulation of vascular cell proliferation and survival. 20,23 The present study was conducted in a murine model of unilateral limb ischemia to explore the therapeutic potential of NCX 4016 on reparative angiogenesis. Results indicate that NO-releasing aspirin improves vascular regeneration, prevents endothelial apoptosis, and reduces oxidative stress. Thus, this new drug may have clinical value for the treatment of peripheral vascular disease. MethodsAll procedures complied with the standards stated in the Guide for t...

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