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

J Mol Cell Cardiol. 2007 Sep;43(3):344-53. doi: 10.1016/j.yjmcc.2007.06.010. Epub 2007 Jun 30.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / therapeutic use*
  • Animals
  • Cardiotonic Agents / therapeutic use*
  • Case-Control Studies
  • Disease Models, Animal
  • Echocardiography, Doppler
  • Glutathione / deficiency
  • Glutathione / metabolism
  • Heart Failure / drug therapy*
  • Male
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / etiology
  • Myocardial Infarction / pathology
  • Oxidative Stress / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors*
  • Sphingomyelin Phosphodiesterase / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism


  • Cardiotonic Agents
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Sphingomyelin Phosphodiesterase
  • Glutathione
  • Acetylcysteine