Lipoxygenase metabolism of arachidonic acid in ischémic 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 ischémie preconditioning (PC), and we report, in perfused rat heart, that both PC and the PKC activator 1,2-dioctanoyl-sw-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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology
Volume276
Issue number6 PART 2
StatePublished - 1999

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Arachidonate Lipoxygenases
Arachidonate 12-Lipoxygenase
Protein Kinase C
Glycerol
Ventricular Pressure
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Lipoxygenase Inhibitors
Acids
Eicosanoids
Protein C Inhibitor
Protein Kinase Inhibitors
Ischemia
Rabbits

ASJC Scopus subject areas

  • Physiology (medical)

Cite this

Lipoxygenase metabolism of arachidonic acid in ischémic preconditioning and PKC-induced protection in heart. / Chen, Weina; Glasgow, Wayne; Murphy, Elizabeth; Steenbergen, Charles.

In: American Journal of Physiology, Vol. 276, No. 6 PART 2, 1999.

Research output: Contribution to journalArticle

Chen, Weina ; Glasgow, Wayne ; Murphy, Elizabeth ; Steenbergen, Charles. / Lipoxygenase metabolism of arachidonic acid in ischémic preconditioning and PKC-induced protection in heart. In: American Journal of Physiology. 1999 ; Vol. 276, No. 6 PART 2.
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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 isch{\'e}mie preconditioning (PC), and we report, in perfused rat heart, that both PC and the PKC activator 1,2-dioctanoyl-sw-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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AB - 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 ischémie preconditioning (PC), and we report, in perfused rat heart, that both PC and the PKC activator 1,2-dioctanoyl-sw-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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