Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat.
BACKGROUND
Both statins and thiazolidinediones have antiinflammatory properties. However, the exact mechanisms underlying these effects are unknown. We investigated whether atorvastatin (ATV) and pioglitazone (PIO) increase the myocardial content of lipoxin-A4 and 15(R)-epi-lipoxin-A4 (15-epi-LXA4), both arachidonic acid products with strong antiinflammatory properties.


RESULTS
In experiment 1, rats received 3-day pretreatment with water; PIO 2, 5, or 10 mg x kg(-1) x d(-1); ATV 2, 5, or 10 mg x kg(-1) x d(-1); or PIO 10 mg x kg(-1) x d(-1)+ATV 10 mg x kg(-1) x d(-1). In experiment 2, rats received water; PIO 10 mg x kg(-1) x d(-1)+ATV 10 mg x kg(-1) x d(-1); PIO+ATV and valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor; PIO+ATV and zileuton, a selective 5-lipoxygenase inhibitor; or zileuton alone. There were 4 rats in each group. Hearts were harvested and analyzed for myocardial lipoxin-A4 and 15-epi-LXA4 levels and for COX-2 and 5-lipoxygenase protein expression. ATV and PIO at 5 and 10 mg x kg(-1) . d(-1) significantly increased myocardial 15-epi-LXA4 levels compared with the sham-treated group (0.51 +/- 0.02 ng/mg). Myocardial 15-epi-LXA4 were significantly higher in the PIO+ATV group (1.29 +/- 0.02 ng/mg; P < 0.001 versus each other group). Both valdecoxib and zileuton abrogated the PIO+ATV increase in 15-epi-LXA4, whereas zileuton alone had no effect. PIO, ATV, and their combination resulted in a small increase in myocardial lipoxin-A4 levels, which was not statistically significant. ATV alone or in combination with PIO markedly augmented COX-2 expression. PIO had a much smaller effect on COX-2 expression. Myocardial expression of 5-lipoxygenase was not altered by PIO, ATV, or their combination.


CONCLUSIONS
Both PIO and ATV increase myocardial levels of 15-epi-LXA4, a mediator with antiinflammatory properties. This finding may explain the antiinflammatory properties of both PIO and ATV.
Birnbaum
Yochai
Y
Division of Cardiology, University of Texas Medical Branch, 5106 John Sealy Annex, 301 University Blvd, Galveston, Texas 77555-0553, USA. yobirnba@utmb.edu
Ye
Yumei
Y
Lin
Yu
Y
Freeberg
Sheldon Y
SY
Nishi
Shawn P
SP
Martinez
Juan D
JD
Huang
Ming-He
MH
Uretsky
Barry F
BF
Perez-Polo
Jose R
JR
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D000069059:Atorvastatin; D006321:Heart / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D044045:Lipoxins / Q000096:biosynthesis*; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D000077205:Pioglitazone; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D006538:Heptanoic Acids; D044045:Lipoxins; D011758:Pyrroles; D045162:Thiazolidinediones; C040527:lipoxin A4; D000069059:Atorvastatin; D000077205:Pioglitazone