Abstract 12793: Glutathionylation of Erythrocyte Na-K Pump in Heart Failure: A Novel Biomarker That Reflects a Key Oxidative Abnormality In the Heart
Background: Novel biomarkers may aid the diagnosis and surveillance of patients with heart failure (HF), as well as guide effective targeting of therapy. The most promising biomarkers closely correlate with the pathophysiological process of the disease. We have identified glutathionylation, a reversible oxidative modification, of the cardiac Na-K pump’s β1 subunit as the molecular mediator of Na-K pump inhibition in disease states characterized by elevated oxidative stress, including HF. Glutathionylation-induced pump inhibition is likely to contribute to the raised intracellular Na+ and the dysregulation of Ca2+ characteristic of the HF syndrome. We hypothesized that the erythrocyte Na-K pump undergoes the same oxidative inhibition, and this would closely reflect that in the heart, providing a circulating marker for this key molecular event.
Methods and results: The Na-K pump’s β1 subunit was readily detectable in erythrocytes and was glutathionylated (eβ1-GSS) in both rabbits and humans under conditions of oxidative stress. We developed an ELISA assay for reproducible quantification. In a rabbit infarct model of HF, eβ1-GSS was 75% higher than in control (1693±108 versus 972±69; p<0.001; n=6) and correlated with the oxidative Na-K pump inhibition in cardiac myocytes (mβ1-GSS; r=0.851; n=18; p<0.001), as well as BNP (r=0.755; n=18; p<0.001). There was a negative correlation between eβ1-GSS and LV ejection fraction (r=-0.842; n=17; p<0.001). In hospitalized HF patients eβ1-GSS was ∼3 fold higher than healthy controls (3167 ± 164 U vs 1018 ± 20 U; n=16; p<0.001) in association with a ~50% reduction in erythrocyte Na-K pump activity (52.3 ± 4 vs 96.7 ± 2; n=16; p<0.001), and there was a positive correlation between eβ1-GSS and NT-proBNP (r=0.65; n=13; p=0.017).
Conclusion: eβ1-GSS is substantially elevated in both an animal model of HF and in patients hospitalized with HF, and closely correlates with severity. Its potential as a biomarker for HF is supported by its direct correlation with oxidative Na-K pump inhibition in the heart. eβ1-GSS may be have additive prognostic value over current biomarkers particularly for detection of incident HF in the asymptomatic early stages of disease.
- © 2012 by American Heart Association, Inc.