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(1alpha) (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+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(1alpha) 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(1alpha). PIO+ATV increased 15-epi-LXA4 and 6-keto-PGF(1alpha) levels. ASA and 1400 W attenuated the effects of PIO+ATV on 15-epi-LXA4 and 6-keto-PGF(1alpha). 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(1alpha) was attenuated. In conclusion, COX2 acetylation by ASA shifts enzyme from producing 6-keto-PGF(1alpha) to 15-epi-LXA4. In contrast, S-nitrosylation by PIO+ASA augments the production of both 15-epi-LXA4 and 6-keto-PGF(1alpha). However, when COX2 is both acetylated and S-nitrosylated, it is inactivated. We suggest potential adverse interactions among statins, thiazolidinediones, and high-dose ASA.
Birnbaum
Yochai
Y
The Division of Cardiology, University of Texas Medical Branch, Galveston, TX 77555-0553, USA. yobirnba@utmb.edu
Ye
Yumei
Y
Lin
Yu
Y
Freeberg
Sheldon Y
SY
Huang
Ming-He
MH
Perez-Polo
Jose R
JR
Uretsky
Barry F
BF
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology*; D000069059:Atorvastatin; D001710:Biotin / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006538:Heptanoic Acids / Q000737:chemistry / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D044045:Lipoxins / Q000096:biosynthesis* / Q000737:chemistry; D008297:Male; D009206:Myocardium / Q000201:enzymology; D009603:Nitroso Compounds / Q000378:metabolism; D000077205:Pioglitazone; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D044045:Lipoxins; D009603:Nitroso Compounds; D011758:Pyrroles; D045162:Thiazolidinediones; C040527:lipoxin A4; D001710:Biotin; D000069059:Atorvastatin; D051546:Cyclooxygenase 2; D001241:Aspirin; D000077205:Pioglitazone