Leukocyte-type 12-lipoxygenase-deficient mice show impaired ischemic preconditioning-induced cardioprotection.
To investigate the role of 12-lipoxygenase in preconditioning, we examined whether hearts lacking the "leukocyte-type" 12-lipoxygenase (12-LOKO) would be protected by preconditioning. In hearts from wild-type (WT) and 12-LOKO mice, left ventricular developed pressure (LVDP) and (31)P NMR were monitored during treatment (+/-preconditioning) and during global ischemia and reperfusion. Postischemic function (rate-pressure product, percentage of initial value) measured after 20 min of ischemia and 40 min of reperfusion was significantly improved by preconditioning in WT hearts (78 +/- 12% in preconditioned vs. 44 +/- 7% in nonpreconditioned hearts) but not in 12-LOKO hearts (47 +/- 7% in preconditioned vs. 33 +/- 10% in nonpreconditioned hearts). Postischemic recovery of phosphocreatine was significantly better in WT preconditioned hearts than in 12-LOKO preconditioned hearts. Preconditioning significantly reduced the fall in intracellular pH during sustained ischemia in both WT and 12-LOKO hearts, suggesting that attenuation of the fall in pH during ischemia can be dissociated from preconditioning-induced protection. Necrosis was assessed after 25 min of ischemia and 2 h of reperfusion using 2,3,5-triphenyltetrazolium chloride. In WT hearts, preconditioning significantly reduced the area of necrosis (26 +/- 4%) compared with nonpreconditioned hearts (62 +/- 10%) but not in 12-LOKO hearts (85 +/- 3% in preconditioned vs. 63 +/- 11% in nonpreconditioned hearts). Preconditioning resulted in a significant increase in 12(S)-hydroxyeicosatetraenoic acid in WT but not in 12-LOKO hearts. These data demonstrate that 12-lipoxygenase is important in preconditioning.
Gabel
S A
SA
National Institute of Environmental Health Sciences, Research Triangle Park 27709, Durham, North Carolina 27710, USA.
London
R E
RE
Funk
C D
CD
Steenbergen
C
C
Murphy
E
E
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D019157:Ischemic Preconditioning, Myocardial; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology; D009336:Necrosis
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000255:Adenosine Triphosphate; D001092:Arachidonate 12-Lipoxygenase