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J. Biol. Chem., Vol. 281, Issue 22, 15110-15120, June 2, 2006

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Redox Activation of Aldose Reductase in the Ischemic Heart^*

Karin Kaiserova, Sanjay Srivastava, Joseph D. Hoetker, Sunday O. Awe, Xian-Liang Tang, Jian Cai^¶, and Aruni Bhatnagar¹

From the Institute of Molecular Cardiology, Departments of Physiology and Biophysics and ^¶Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202

Aldose reductase (AR) reduces cytotoxic aldehydes and glutathione conjugates of aldehydes derived from lipid peroxidation. Its inhibition has been shown to increase oxidative injury and abolish the late phase of ischemic preconditioning. However, the mechanisms by which ischemia regulates AR activity remain unclear. Herein, we report that rat hearts subjected to ischemia, in situ or ex vivo, display a 2–4-fold increase in AR activity. The AR activity was not further enhanced by reperfusion. Activation increased V_max of the enzyme without affecting the K_m and decreased the sensitivity of the enzyme to inhibition by sorbinil. Enzyme activation could be prevented by pretreating the hearts with the radical scavenging thiol, N-(2-mercaptoproprionyl)glycine or the superoxide dismutase mimetic, Tiron, or by treating homogenates with dithiothreitol. In vitro, the recombinant enzyme was activated upon treatment with H₂O₂ and the activated, but not the native enzyme, formed a covalent adduct with the sulfenic acid-specific reagent dimedone. The enzyme activity in the ischemic, but not the nonischemic heart homogenates was inhibited by dimedone. Separation of proteins from hearts subjected to coronary occlusion by two-dimensional electrophoresis and subsequent matrix-assisted laser desorption ionization time-of-flight/mass spectrometry analysis revealed the formation of sulfenic acids at Cys-298 and Cys-303. These data indicate that reactive oxygen species formed in the ischemic heart activate AR by modifying its cysteine residues to sulfenic acids.

Received for publication, January 27, 2006 , and in revised form, March 13, 2006.

^* This work was supported in part by National Institutes of Health Grants HL55477, HL59378, HL65618, and ES11860. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 502-852-5966; Fax: 502-852-3663; E-mail: aruni{at}louisville.edu.

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