RT Journal Article
SR Electronic
T1 Cooperation between Aspirin-Triggered Lipoxin and Nitric Oxide (NO) Mediates Antiadhesive Properties of 2-(Acetyloxy)benzoic Acid 3-(Nitrooxymethyl)phenyl Ester (NCX-4016) (NO-Aspirin) on Neutrophil-Endothelial Cell Adherence
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1174
OP 1182
DO 10.1124/jpet.103.063651
VO 309
IS 3
A1 Stefano Fiorucci
A1 Eleonora Distrutti
A1 Andrea Mencarelli
A1 Giovanni Rizzo
A1 Anna Rita Di Lorenzo
A1 Monia Baldoni
A1 Piero del Soldato
A1 Antonio Morelli
A1 John L. Wallace
YR 2004
UL http://jpet.aspetjournals.org/content/309/3/1174.abstract
AB 2-(Acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a nitric oxide (NO)-releasing derivative of aspirin that inhibits cyclooxygenase (COX) activity and releases NO. Acetylation of COX-2 by aspirin activates a transcellular biosynthetic pathway that switches eicosanoid biosynthesis from prostaglandin E2 to 15-epi-lipoxin (LX)A4 or aspirin-triggered lipoxin (ATL). Here, we demonstrate that exposure of neutrophil (PMN)/human umbilical vein endothelial cell (HUVEC) cocultures to aspirin and NCX-4016 triggers ATL formation and inhibits cell-to-cell adhesion induced by endotoxin (LPS) and interleukin (IL)-1β by 70 to 90%. However, although selective and nonselective COX-2 inhibitors (celecoxib, rofecoxib, and naproxen) or N-t-butoxycarbonyl-methionine-leucine-phenylalanine (Boc-1), an LXA4 receptor antagonist, reduced the antiadhesive properties of aspirin by ≈70%, antiadhesive effects of NCX-4016 were only marginally affected (≈30%) by COX inhibitors and Boc-1, implying that COX-independent mechanisms mediate the antiadhesive properties of NCX-4016. Indeed, NCX-4016 causes a long-lasting (up to 12 h) release of NO and cGMP accumulation in HUVEC. Scavenging NO with 10 mM hemoglobin, in the presence of celecoxib, reduced the antiadhesive properties of NCX-4016 by ≈80%. Confirming a role for NO, the NO donor diethylenetriamine-NO also inhibited PMN/HUVEC adhesion by ≈80%. NCX-4016, but not aspirin, decreased DNA binding of nuclear factor-κB (NF-κB) on gel shift analysis and HUVEC's overexpression of CD54 and CD62E induced by LPS/IL-1β. Reduction of binding of the two NF-κB subunits p50-p50 and p50-p65 was reversed by dithiothreitol, implying S-nitrosylation as mechanism of inhibition. In summary, our results support that ATL and NO are formed at the PMN/HUVEC interface after exposure to NCX-4016 and mediate the antiadhesive properties of this compound. The American Society for Pharmacology and Experimental Therapeutics