Original ContributionPolyol pathway mediates iron-induced oxidative injury in ischemic–reperfused rat heart
Introduction
There is a large body of evidence demonstrating that the polyol pathway contributes to the pathogenesis of various diabetic complications [1], [2]. Aldose reductase (AR; EC 1.1.1.21), the first and rate-limiting enzyme of the pathway, reduces glucose to sorbitol with the oxidation of its cofactor NADPH to NADP. Sorbitol dehydrogenase (SDH: EC 1.1.1.14), the second enzyme of the polyol pathway then converts sorbitol to fructose with the concomitant reduction of NAD+ to NADH [3]. Under hyperglycemia, increase flux of glucose through the polyol pathway leads to the depletion of NADPH and NAD+. Decrease in the level of NADPH is thought to lead to a decreased level of GSH because NADPH is also the cofactor for glutathione reductase that regenerates GSH from oxidized glutathione [4]. Decreased levels of NAD+ may lead to reduction in ATP levels [5]. These changes are thought to contribute to diabetes-induced tissue damage in the ocular lens, retina, peripheral nerves, and kidney.
AR has also been shown to play a key role in ischemia/reperfusion (I/R) induced injury of the heart [6], [7], [8] and brain [9]. The protective effect of AR inhibition against myocardial I/R injury is thought to be due to normalization of cytosolic NADH/NAD+ ratio, thereby preventing the depletion of ATP and redox imbalance. This is deduced from the fact that inhibition of SDH also protects the heart against I/R injury [10]. SDH competes with glyceraldehydes-3-phosphate dehydrogenase (GAPDH) for NAD+. Inhibition of SDH attenuates the increased cytosolic NADH/NAD+ ratio, and increases glycolysis. Thus, pharmacological inhibition of AR and SDH presents a novel adjunctive approach for protection against ischemic hearts.
In the course of our studies on the effect of AR deficiency on various tissues we found that lack of AR attenuates the increase in transferrin (Tf) level observed in I/R tissues [unpublished, 9], suggesting that AR might contribute to tissue damage by enhancing iron-catalyzed generation of oxygen free radicals. It is well established that iron (Fe) generates highly toxic hydroxyl radicals through Fenton chemistry [11], [12]. However, Fe is also essential for many enzymatic functions. Fe homeostasis is thus crucial for the cells to balance the need for Fe against its toxicity. The maintenance of intracellular iron homeostasis depends on the balanced expression of Tf, the extracellular carrier of Fe, transferrin receptor (TfR) that internalizes Tf and Fe along with it, and ferritin, which stores intracellular Fe in nontoxic form.
The expression of TfR is regulated by intracellular Fe level. Low Fe levels increase TfR synthesis because iron regulatory protein (IRP) binds to the iron responsive elements (IRE) at the 3′-end of its mRNA to protect it from degradation. Transcription of TfR mRNA is also enhanced [13]. Besides IRP, hypoxia-inducible factor-1 alpha (HIF-1α) has been shown to activate the transcription of TfR genes in response to hypoxia in hepatoma cells [13]. Induction of HIF-1α has been observed in postischemic rat liver and heart [14]. It was suggested that HIF-1α mediated an increase in the TfR level and the consequent increased Fe uptake contributes to free radical-induced damages during I/R [13].
In this report we explored the link between AR activity and Tf increase in I/R hearts of rats. We found that blocking AR or SDH activity reduced the infract size, and attenuated the induction of HIF-1α, TfR, and cellular Fe accumulation in the I/R heart. Further, treatment with niacin, the precursor in the synthesis of NAD+, also reduced HIF-1α and TfR levels. These results indicate that, in the I/R heart, polyol pathway-mediated depletion of NAD+ leads to the induction of HIF-1α, which causes the increase in TfR and Tf-bound Fe uptake, contributing to Fe-catalyzed oxidative damage.
Section snippets
Experimental animals
Sprague-Dawley male rats weighing between 250 and 300 g were supplied by the Laboratory Animal Unit, University of Hong Kong. Inhibition of AR was achieved by intraperitoneal injection of an AR inhibitor (zopolrestat, 100 mg/kg), an hour before the coronary artery ligation (CAL), and the dosage we used was based on a prior dose–response experiment shown in Fig. 1a. Inhibition of SDH was achieved by oral administration of a SDH inhibitor, (CP-470,711, 2 mg/kg/day), for 5 days before in vivo I/R,
Inhibition of the polyol pathway reduced the size of infarct area in the I/R hearts
I/R of the rat hearts was performed as described under Materials and methods. Forty-five minutes of ischemia was followed by 4 h of reperfusion. As shown in Fig. 1c, treatment with an inhibitor of AR, the first enzyme of the pathway, significantly reduced the infarct size as reported previously in a mouse model [20]. Inhibition of SDH, the second enzyme of the pathway also reduced the infarct size, indicating that the polyol pathway enzymes, particularly SDH, contribute significantly to
Discussion
A number of studies have shown that the polyol pathway plays a major role in I/R injury of the heart. It was thought to be due to depletion of ATP as a consequence of increased NADH/NAD+ ratio [6], [7], [10], [20]. Here we demonstrate that during I/R, polyol pathway activity increases the level of TfR, leading to increased cellular uptake of Tf and Fe, and exacerbates tissue damage. The increased level of TfR is most likely due to the induction of HIF-1α, which is known to activate the
Acknowledgment
We thank Mr. C.P. Mok for his assistance.
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