Aspirin (ASA) inhibits cycloxygenase-1 and modifies cycloxygenase-2 (COX2) by acetylation at Ser530, leading to a shift from production of PGH2, the precursor of prostaglandin, to 15-R-HETE which is converted by 5-lipoxygenase to 15-epi-lipoxin A4 (15-epi-LXA4), a potent anti-inflammatory mediator. Both atorvastatin (ATV) and pioglitazone (PIO) increase COX2 expression. ATV activates COX2 by S-nitrosylation at Cys526 to produce 15-epi-LXA4 and 6-keto-PGF1α (the stable metabolite of PGI2). We assessed the effect of ASA on the myocardial production of 15-epi-LXA4 and PGI2 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 + 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-PGF1α 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-PGF1α. PIO + ATV increased 15-epi-LXA4 and 6-keto-PGF1α levels. ASA and 1400 W attenuated the effects of PIO + ATV on 15-epi-LXA4 and 6-keto-PGF1α. 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-PGF1α was attenuated. In conclusion, COX2 acetylation by ASA shifts enzyme from producing 6-keto-PGF1α to 15-epi-LXA4. In contrast, S-nitrosylation by PIO + ASA augments the production of both 15-epi-LXA4 and 6-keto-PGF1α. However, when COX2 is both acetylated and S-nitrosylated, it is inactivated. We suggest potential adverse interactions among statins, thiazolidinediones, and high-dose ASA.
|Original language||English (US)|
|Number of pages||10|
|Journal||Prostaglandins and Other Lipid Mediators|
|State||Published - Feb 2007|
- 15-Epi-lipoxin A
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