Aldose reductase (AR), a member of the
aldo-keto reductase superfamily, has been shown to metabolize toxic
aldehydes generated by lipid peroxidation, suggesting that it may serve as an
antioxidant defense. To investigate its role in the late phase of ischemic preconditioning (PC), conscious rabbits underwent 6 cycles of 4-minute
coronary occlusion/4-minute reperfusion. Twenty-four hours later, there was a marked increase in AR
protein and activity and in the myocardial content of
sorbitol, a unique product of AR catalysis. Pretreatment with
N(omega)-nitro-L-arginine, a
nitric oxide synthase inhibitor, or
chelerythrine, a
protein kinase C inhibitor (both given at doses that block late PC in this model), prevented the increase in AR
protein 24 hours later, demonstrating that ischemic PC upregulates AR via
nitric oxide- and
protein kinase C-dependent signaling pathways. The AR-selective inhibitors
tolrestat and
sorbinil prevented AR-mediated accumulation of
sorbitol and abrogated the
infarct-sparing effect of late PC, demonstrating that enhanced AR activity is necessary for this cardioprotective phenomenon to occur. Inhibition of AR did not affect
infarct size or the myocardial accumulation of the lipid peroxidation product 4-hydroxy
trans-2-nonenal (HNE) in nonpreconditioned rabbits. The accumulation of HNE was inhibited by late PC, and this effect was abrogated by
sorbinil. Taken together, these results establish AR as an essential mediator of late PC. Furthermore, the data suggest that
myocardial ischemia/
reperfusion injury is due in part to the generation of lipid peroxidation products and that late PC diminishes this source of injury by upregulating AR.