RGD Reference Report - Redox activation of aldose reductase in the ischemic heart. - Rat Genome Database

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Redox activation of aldose reductase in the ischemic heart.

Authors: Kaiserova, K  Srivastava, S  Hoetker, JD  Awe, SO  Tang, XL  Cai, J  Bhatnagar, A 
Citation: Kaiserova K, etal., J Biol Chem. 2006 Jun 2;281(22):15110-20. Epub 2006 Mar 27.
RGD ID: 1626092
Pubmed: PMID:16567803   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M600837200   (Journal Full-text)

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 Vmax of the enzyme without affecting the Km 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Myocardial Ischemia  ISOAkr1b1 (Rattus norvegicus)1626092; 1626092protein:increased activity:heartRGD 
Myocardial Ischemia  IDA 1626092protein:increased activity:heartRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to organic substance  IDA 1626092 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Akr1b1  (aldo-keto reductase family 1 member B1)

Genes (Mus musculus)
Akr1b1  (aldo-keto reductase family 1 member B)

Genes (Homo sapiens)
AKR1B1  (aldo-keto reductase family 1 member B)


Additional Information