Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats.
Deficiency in cellular thiol tripeptide glutathione (L-gamma glutamyl-cysteinyl-glycine) determines the severity of several chronic and inflammatory human diseases that may be relieved by oral treatment with the glutathione precursor N-acetylcysteine (NAC). Here, we showed that the left ventricle (LV) of human failing heart was depleted in total glutathione by 54%. Similarly, 2-month post-myocardial infarction (MI) rats, with established chronic heart failure (CHF), displayed deficiency in LV glutathione. One-month oral NAC treatment normalized LV glutathione, improved LV contractile function and lessened adverse LV remodelling in 3-month post-MI rats. Biochemical studies at two time-points of NAC treatment, 3 days and 1 month, showed that inhibition of the neutral sphingomyelinase (N-SMase), Bcl-2 depletion and caspase-3 activation, were key, early and lasting events associated with glutathione repletion. Attenuation of oxidative stress, downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and its TNF-R1 receptor were significant after 1-month NAC treatment. These data indicate that, besides glutathione deficiency, N-SMase activation is associated with post-MI CHF progression, and that blockade of N-SMase activation participates to post-infarction failing heart recovery achieved by NAC treatment. NAC treatment in post-MI rats is a way to disrupt the vicious sTNF-alpha/TNF-R1/N-SMase cycle.
Adamy
Christophe
C
Inserm, U841, Créteil, F-94000, France.
Mulder
Paul
P
Khouzami
Lara
L
Andrieu-abadie
Nathalie
N
Defer
Nicole
N
Candiani
Gabriele
G
Pavoine
Catherine
C
Caramelle
Philippe
P
Souktani
Richard
R
Le Corvoisier
Philippe
P
Perier
Magali
M
Kirsch
Matthias
M
Damy
Thibaud
T
Berdeaux
Alain
A
Levade
Thierry
T
Thuillez
Christian
C
Hittinger
Luc
L
Pecker
Françoise
F
D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002316:Cardiotonic Agents; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D013108:Sphingomyelin Phosphodiesterase; D005978:Glutathione; D000111:Acetylcysteine