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This dissertation, Polyol Pathway Contributes to Iron-induced Oxidative Damage in Ischemia-reperfused Rat Hearts by 鄧偉豪, Wai-ho, Jack, Tang, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: ___________________________________________________________________________________ Abstract of the thesis entitled Polyol pathway contributes to Fe-induced oxidative damage in I/R rat hearts Submitted by Tang, Jack Wai Ho for the degree of Master of philosophy at The University of Hong Kong August, 2007 Background: Ischemia-reperfusion (I/R) induced heart injury is a major cause of morbidity and mortality in the developed countries. Recently, it has been shown that polyol pathway is involved in I/R-induced myocardial infarction, and the mechanism is thought to be due to depletion of ATP level. We serendipitously found that lack of aldose reductase (ALR2), the first and rate-limiting enzyme of the polyol pathway attenuated the increase in transferrin (Tf) level in I/R tissues, suggesting that ALR2 may contribute to iron-catalyzed free radical-induced damage. Methods & Results: In this report we show that inhibition of ALR2 or sorbitol dehydrogenase (SDH), the second enzyme in the polyol pathway both attenuated the I/R mediated increases in HIF-1α (hypoxia inducible factor), Tf, TfR (Tf receptor), intracellular iron content and reduced the I/R-induced infract area of the heart. Further, administration of niacin, which replenishes NAD, the co-factor for SDH, also normalized TfR and HIF-1α levels in I/R heart. Conclusion: These results suggest that during I/R polyol pathway activity increases the cytosolic NADH/NAD ratio. This activates HIF-1α that induces the expression of TfR, which in turn increases Tf uptake and iron accumulation that exacerbates tissue damage during the late phase of reperfusion. This was confirmed by the fact that administration of deferoxamine, an iron chelator, attenuated the I/R-induced myocardial infarction. (214 words) ___________________________________________________________________________________ P.1 DOI: 10.5353/th_b3955802 Subjects: PolyolsReperfusion injuryIschemiaIron - Physiological effectMice as laboratory animals

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