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Improvement of the chronic failing heart via compensation for glutathione deficiency
Author(s) -
Pecker Francoise,
Adamy Christophe,
Mulder Paul,
Candiani Gabriele,
AndrieuAbadie Nathalie,
Pavoine Catherine,
Defer Nicole,
Levade Thierry,
Thuillez Christian,
Hittinger Luc
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1447-c
Subject(s) - glutathione , tumor necrosis factor alpha , heart failure , reactive oxygen species , medicine , pharmacology , endocrinology , oxidative stress , chemistry , biochemistry , enzyme
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.