Polyol pathway mediates iron-induced oxidative injury in ischemic-reperfused rat heart

Free Radic Biol Med. 2008 Sep 1;45(5):602-10. doi: 10.1016/j.freeradbiomed.2008.05.003. Epub 2008 May 15.


Recent studies have shown that the polyol pathway is involved in ischemia-reperfusion (I/R)-induced myocardial infarction, but the mechanism is unclear. We previously found that lack of aldose reductase (AR), the first enzyme of the polyol pathway, attenuated the increase in transferrin (Tf) level in I/R brain, suggesting that AR contributes to iron-catalyzed free radical-induced damage. We therefore investigated if this mechanism occurs in I/R hearts. We found that inhibition of AR or sorbitol dehydrogenase (SDH), the second enzyme of the polyol pathway, both attenuated the I/R-mediated increases in HIF-1alpha, Tf, TfR, and intracellular iron content and reduced the I/R-induced infarct area of the heart. Further, administration of niacin, which replenishes NAD+, the cofactor for SDH, also normalized TfR and HIF-1alpha levels in I/R hearts. These results suggest that during I/R polyol pathway activity increases the cytosolic NADH/NAD+ ratio. This activates HIF-1alpha that induces the expression of TfR, which in turn increases Tf uptake and iron accumulation and exacerbates oxidative damage that increases the lipid peroxidation. This was confirmed by the fact that administration of the iron chelator deferoxamine attenuated the I/R-induced myocardial infarction.

MeSH terms

  • Aldehyde Reductase / metabolism
  • Animals
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Iron / metabolism*
  • L-Iditol 2-Dehydrogenase / metabolism
  • Male
  • Malondialdehyde / metabolism
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control
  • Niacin / pharmacology
  • Oxidative Stress*
  • Polymers / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Transferrin / metabolism
  • Signal Transduction*
  • Superoxides / metabolism
  • Transferrin / metabolism


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Polymers
  • Receptors, Transferrin
  • Transferrin
  • polyol
  • Superoxides
  • Niacin
  • Malondialdehyde
  • Iron
  • L-Iditol 2-Dehydrogenase
  • Aldehyde Reductase