Aspirin augments 15-epi-lipoxin A4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A4 in the rat heart

Aspirin (ASA) inhibits cycloxygenase-1 and modifies cycloxygenase-2 (COX2) by acetylation at Ser(530), leading to a shift from production of PGH(2), the precursor of prostaglandin, to 15-R-HETE which. is converted by 5-lipoxygenase to 15-epi-lipoxin A(4) (15-epi-LXA4), a potent anti-inflammatory mediator. Both atorvastatin (ATV) and pioglitazone (PIO) increase COX2 expression. ATV activates COX2 by S-nitrosylation at Cys(526) to produce 15-epi-LXA4 and 6-keto-PGF(1 alpha) (the stable metabolite of PGI(2)). We assessed the effect of ASA on the myocardial production of 15-epi-LXA4 and PGI(2) after induction by lipopolysaccharide (LPS) or PIO+ATV. Sprague-Dawley rats were pretreated with: control; ASA 10 mg/kg; ASA 50 mg/kg; LPS alone; LPS + ASA 10 mg/kg; LPS + ASA 50 mg/kg; LPS + ASA 200 mg/kg; PIO (10 mg/kg/d) + ATV (10 mg/kg/d); PIO divided by ATV + ASA 10 mg/kg; PIO + ATV + ASA 50 mg/kg; PIO + ATV + ASA 50 mg/kg + 1400 W, a specific iNOS inhibitor; or PIO + ATV + 1400 W. ASA alone had no effect on myocardial 15-epi-LXA4. LPS increased 15-epi-LXA4 and 6-keto-PGF(1 alpha) levels. ASA (50 mg/kg and 200 mg/kg, but not 10 mg/kg) augmented the LPS effect on 15-epi-LXA4 but attenuated the effect on 6-keto-PGF(1 alpha). PIO + ATV increased 15-epi-LXA4 and 6-keto-PGF(1 alpha) levels. ASA and 1400 W attenuated the effects of PIO + ATV on 15-epi-LXA4 and 6-keto-PGF(1 alpha). However, when both ASA and 1400 W were administered with PIO + ATV, there was a marked increase in 15-epi-LXA4, whereas the production of 6-keto-PGF(1 alpha) was attenuated. In conclusion, COX2 acetylation by ASA shifts enzyme from producing 6-keto-PGF(1 alpha) to 15-epi-LXA4. In contrast, S-nitrosylation by PIO + ASA augments the production of both 15-epi-LXA4 and 6-keto-PGF(1 alpha). However, when COX2 is both acetylated and S-nitrosylated, it is inactivated. We suggest potential adverse interactions among statins, thiazolidinediones, and high-dose ASA. (c) 2006 Elsevier Inc. All rights reserved.