Lipid peroxidation-derived aldehydes and oxidative stress in the failing heart: Role of aldose reductase

Sanjay Srivastava, Bysani Chandrasekar, Aruni Bhatnagar, Sumanth D. Prabhu

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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.

Original languageEnglish
Pages (from-to)H2612-H2619
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume283
Issue number6 52-6
DOIs
StatePublished - Dec 1 2002

Keywords

  • Tonicity-responsive enhancer binding protein
  • Ventricular remodeling

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