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
Inserm, U841, Créteil, F-94000, France.
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.
细胞内硫醇三肽谷胱甘肽（L-γ-谷氨酰-半胱氨酰-甘氨酸）缺乏决定了几种慢性和炎症性人类疾病的严重程度，口服谷胱甘肽前体N-乙酰半胱氨酸（NAC）治疗可能会缓解这些疾病。在此，我们发现人类衰竭心脏的左心室（LV）总谷胱甘肽减少了54%。同样，心肌梗死（MI）2个月后的大鼠，已确立慢性心力衰竭（CHF），其左心室谷胱甘肽缺乏。对MI后3个月的大鼠进行为期1个月的口服NAC治疗，可使左心室谷胱甘肽恢复正常，改善左心室收缩功能，并减轻左心室不良重塑。在NAC治疗的两个时间点，即3天和1个月时进行的生化研究表明，抑制中性鞘磷脂酶（N-SMase）、Bcl-2耗竭和半胱天冬酶-3激活是与谷胱甘肽补充相关的关键、早期和持久事件。NAC治疗1个月后，氧化应激减轻、促炎细胞因子肿瘤坏死因子-α（TNF-α）及其TNF-R1受体下调显著。这些数据表明，除了谷胱甘肽缺乏外，N-SMase激活与MI后CHF进展相关，并且阻断N-SMase激活参与了NAC治疗实现的梗死后衰竭心脏恢复。MI后大鼠的NAC治疗是破坏恶性sTNF-α/TNF-R1/N-SMase循环的一种方法。
