Improvement of the chronic failing heart via compensation for glutathione deficiency

Abstract

Glutathione deficiency in chronic heart failure (CHF) has been overlooked. Glutathione neutralizes reactive oxygen species (ROS) production, and is the biological inhibitor of neutral- sphingomyelinase (N-SMase). ROS and N-SMase are both contributors to tumor necrosis factor alpha -receptor-1 (TNF-R1) signalling, determining the deleterious effects of TNF in heart. Differently, TNF-R2 would mediate beneficial effects of TNF. We examined the glutathione status and TNF-R1 and TNF-R2 signalling components in post-myocardial infarction (MI) rats, non-treated or treated, once CHF was established, with the glutathione precursor, N-acetylcysteine (NAC). Oral NAC treatment (50 mg/ day) was started 2-months after coronary artery ligation. Echocardiographic examination indicated well-established CHF in 2-month post-MI rats, associated with a 44% decrease in left ventricular (LV) glutathione. 3-day NAC treatment replenished glutathione to 75% its control value, without improving LV function. 1-month NAC treatment restored glutathione content and enhanced heart function. These benefits were associated with the blockade of TNF-R1 signalling: inversion of the TNF-R1/TNF-R2 and secreted-TNF/membrane-TNF ratios, inhibition of ROS production, N-SMase activity, cell infiltration, and reduction of fibrosis. In conclusion, glutathione replenishment, via NAC treatment, improves failing heart function through TNF-R1 signalling inhibition.