Neutral sphingomyelinase inhibition participates to the benefits of N -acetylcysteine treatment in post-myocardial infarction failing heart rats

• Published in: Journal of molecular and cellular cardiology Vol. 43; no. 3; pp. 344 - 353
• Main Authors: Adamy, Christophe, Mulder, Paul, Khouzami, Lara, Andrieu-abadie, Nathalie, Defer, Nicole, Candiani, Gabriele, Pavoine, Catherine, Caramelle, Philippe, Souktani, Richard, Le Corvoisier, Philippe, Perier, Magali, Kirsch, Matthias, Damy, Thibaud, Berdeaux, Alain, Levade, Thierry, Thuillez, Christian, Hittinger, Luc, Pecker, Françoise
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2007; Elsevier
• Subjects: Acetylcysteine - therapeutic use; Animals; Cardiotonic Agents - therapeutic use; Cardiovascular; Case-Control Studies; Chronic heart failure; Disease Models, Animal; Echocardiography, Doppler; Glutathione; Glutathione - deficiency; Glutathione - metabolism; Heart Failure - drug therapy; Life Sciences; Male; Myocardial Infarction - drug therapy; Myocardial Infarction - etiology; Myocardial Infarction - pathology; N-Acetylcysteine; Neutral sphingomyelinase; Oxidative Stress - drug effects; Rats; Rats, Wistar; Receptors, Tumor Necrosis Factor, Type I - metabolism; RNA, Messenger - metabolism; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelin Phosphodiesterase - metabolism; Time Factors; Tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-alpha; Chronic heart failure; N-Acetylcysteine; Neutral sphingomyelinase; Glutathione
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2007.06.010

Abstract Deficiency in cellular thiol tripeptide glutathione ( l -γ 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-α) 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-α/TNF-R1/N-SMase cycle.