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Phosphorylation of 5‐lipoxygenase by protein kinase A determines whether leukotriene B4 or 15‐epilipoxin A4 mediators are produced in the heart
Author(s) -
Birnbaum Yochai,
Ye Yumei,
Lin Yu,
PerezPolo Jose Regino,
Uretsky Barry F
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1375-d
Subject(s) - phosphorylation , leukotriene b4 , pharmacology , kinase , inflammation , chemistry , medicine , biochemistry
5‐lipoxygenase (5LO) produces both 15‐epilipoxin‐A4 (15ELX), an antiinflammatory mediator, and leukotriene‐B 4 (LTB4). Phosphorylation at Ser 523 by protein kinase A prevents 5LO translocation to the perinuclear membrane. Atorvastatin (ATV) and pioglitazone (PIO) upregulate 15ELX. We assessed whether 5LO phosphorylation (P5LO) by PKA determines whether the cells produce LTB4 or 15ELX. Methods: Rats received either oral PIO (10 mg/kg/d); ATV (10 mg/kg/d); PIO+ATV; or vehicle; 5) or iv lipopolysacharide (LPS) (10 mg/kg). Rat myocardial cells were incubated with ATV+PIO, ATV+PIO+H89 (PKA inhibitor), H89, or vehicle for 8h.Results: ATV (1347±27%), PIO (1407±47%), ATV+PIO (1629±11%), and LPS (185±9%) increased P5LO (p<0.001). ATV+PIO increased P5LO (2069±93%). H89 attenuated the effect of ATV+PIO (409±18%)(p<0.001). ATV+PIO increased 15ELX (2.19±0.04 vs 0.87±0.03 ng/ml in sham). H89 attenuated the effect of PIO+ATV (1.66±0.06) (p<0.001). PIO+ATV (35.58±0.86 pg/ml) and H89 (35.56±0.89) had no effect on LTB4 (sham 36.44±0.25). PIO+ATV+H89 increased LTB4 levels (64.51±0.61) (p<0.001). Immunofluorescence shows that ATV+PIO increased cytosolic expression of 5LO. H89 alone had no effect, whereas in the ATV+PIO+H89 5LO translocated to the perinuclear membrane. Conclusions: Phosphorylation of 5LO determines whether 15ELX (anti‐inflammatory) or LTB4 (inflammatory mediator) are produced.