Tumor necrosis factor alpha and glutathione interplay in chronic heart failure.
The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.
Adamy
C
C
Inserm U581, Université Paris 12, Faculté de Médicine.
Le Corvoisier
P
P
Candiani
G
G
Kirsch
M
M
Pavoine
C
C
Defer
N
N
Bourin
M C
MC
Su
J B
JB
Vermes
E
E
Hittinger
L
L
Pecker
E
E
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002316:Cardiotonic Agents; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione; D000111:Acetylcysteine