title: Lipid peroxidation-derived aldehydes and oxidative stress in the failing heart: role of aldose reductase.
abstract: 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 h or 4 wk of rapid left ventricular (LV) pacing (early and late HF, respectively). Six unpaced dogs served as controls. In early HF, there was subtle depression of LV performance (maximum rate of LV pressure rise, 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 >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 posttranslational 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.
authors.affiliation: Department of Medicine/Cardiology, University of Louisville Health Sciences Center, Kentucky 40202, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D002304:Cardiac Pacing, Artificial; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics; D015227:Lipid Peroxidation; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D000447:Aldehydes; D012333:RNA, Messenger; D015534:Trans-Activators; D004247:DNA; D000449:Aldehyde Reductase