Lipoxygenase metabolism of arachidonic acid in ischemic preconditioning and PKC-induced protection in heart.
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.
Chen
W
W
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Glasgow
W
W
Murphy
E
E
Steenbergen
C
C
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects; D004075:Diglycerides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D016859:Lipoxygenase Inhibitors; D008297:Male; D010725:Phosphocreatine / Q000378:metabolism; D011493:Protein Kinase C / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D004075:Diglycerides; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D010725:Phosphocreatine; C044295:1,2-dioctanoylglycerol; D016718:Arachidonic Acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000255:Adenosine Triphosphate; D001092:Arachidonate 12-Lipoxygenase; D011493:Protein Kinase C