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1 Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710; 2 Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia 31207; and 3 Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709
We tested the hypothesis that activation of
the 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism
contributes to the protective effect of protein kinase C (PKC)
activation and ischemic preconditioning (PC), and we report, in
perfused rat heart, that both PC and the PKC activator
1,2-dioctanoyl-sn-glycerol (DOG)
confer a similar protective effect and stimulate a comparable accumulation of 12-LO metabolites. The 12-LO product,
12(S)-hydroxyeicosatetraenoic acid
[12(S)-HETE],
was increased in DOG-treated (22.8 ± 4.4 ng/g wet wt) and PC hearts
(26.8 ± 5.5 ng/g wet wt) compared with control (13.8 ± 2.1 ng/g
wet wt, P < 0.05), and this increase
was blocked by 12-LO or PKC inhibitors. Both DOG pretreatment and PC
improved recovery of left ventricular developed pressure (LVDP) nearly twofold after 20 min of ischemia; this improvement was blocked by 12-LO inhibitors and was mimicked by infusion of
12-hydroperoxyeicosatetraenoic acid
[12(S)-HpETE; 67 ± 6%
recovery of LVDP vs. 35 ± 3% for untreated hearts]. Also,
the protection afforded by
12(S)-HpETE, as well as by PC, was
attenuated by the K+-channel
blocker 5-hydroxydecanoate, suggesting that the downstream mechanisms
of 12(S)-HpETE-mediated protection
are similar to PC. Furthermore, PC stimulates 12-LO metabolism in
perfused rabbit heart, and 12-LO inhibition blocks PC-induced
cardioprotection. Thus the data suggest that 12-LO metabolism plays an
important role in cardioprotection.
12-lipoxygenase; 12(S)-hydroperoxyeicosatetraenoic acid; eicosanoids
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