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Articles in PresS, published online ahead of print August 22, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00592.2002
Submitted on July 12, 2002
Accepted on August 16, 2002
1 Department of Medicine/Cardiology, University of Louisville, Louisville, KY, USA
2 Department of Medicine/Cardiology, University of Texas Health Science Center, San Antonio, TX, USA
* To whom correspondence should be addressed. E-mail: sprabhu{at}louisville.edu.
Lipid peroxidation-derived aldehydes (LP-DA) can propagate oxidative injury and are detoxified by the aldose reductase (AR) enzyme pathway in myocardium. Whether there are alterations in the AR axis in heart failure (HF) is unknown. Sixteen instrumented dogs were studied before and after either 24 hours or 4 weeks of rapid LV pacing (early and late HF, respectively). Six unpaced dogs served as controls. In early HF, there was subtle depression of LV performance (dP/dtmax, p < 0.05 vs. baseline) but no chamber enlargement, whereas in late HF, there was significant (p < 0.05) contractile depression and LV dilatation. Oxidative stress was increased at both time points, indexed by tissue malondialdehyde, total glutathione, and free C6-C9 LP-DA (p < 0.025 vs. control). AR protein levels and activity decreased progressively during HF (p < 0.025 early/late HF vs. control); however AR mRNA expression decreased only in late HF (p < 0.005 vs. early HF and control). DNA binding of tonicity-responsive enhancer binding protein (TonEBP, a transcriptional regulator of AR) paralleled AR mRNA, declining more than 50% in late HF (p < 0.025 vs. control). We conclude that AR levels and attendant myocardial capacity to detoxify LP-DA decline during the development of HF. In early HF, decreased AR occurs due to a translational or post-translational mechanism, whereas in late HF, reduced TonEBP transcriptional activation and AR downregulation contribute significantly. Reduced AR-mediated LP-DA metabolism contributes importantly to LP-DA accumulation in the failing heart and thus may augment chronic oxidative injury.
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