Lipoxygenase metabolism of arachidonic acid in ischemic preconditioning and PKC-induced protection in heart

Weina Chen, Wayne Glasgow, Elizabeth Murphy, Charles Steenbergen

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)H2094-H2101
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume276
Issue number6 45-6
StatePublished - Jun 1 1999

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Keywords

  • 12(S)-hydroperoxyeicosatetraenoic acid
  • 12-lipoxygenase
  • Eicosanoids

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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