Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats
Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats
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DOI：
10.1016/j.yjmcc.2007.06.010
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发表时间：
2007-09-01
影响因子：
5
通讯作者：
Pecker, Francoise
中科院分区：
文献类型：
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作者：
Adamy, Christophe;Mulder, Paul;Pecker, Francoise
细胞硫醇三肽谷胱甘肽(L-γ-谷氨酰-半胱氨酸-甘氨酸)的缺乏决定了几种慢性和炎症性人类疾病的严重性，这些疾病可以通过口服谷胱甘肽前体N-乙酰半胱氨酸(NAC)来缓解。在这里，我们显示，人类衰竭心脏的左心室(LV)的总谷胱甘肽(GSH)减少了54%。同样，心肌梗死(MI)后2个月的大鼠，确诊为慢性心力衰竭(CHF)，显示左心室谷胱甘肽缺乏。口服NAC 1个月可使服药后3个月大鼠的左心室谷胱甘肽恢复正常，改善左心室收缩功能，减轻不良左室重构。在NAC治疗3天和1个月的两个时间点的生化研究表明，中性鞘氨酸菌素酶(N-sMase)的抑制，即Bcl2耗竭和caspase 3的激活，是谷胱甘肽耗竭的关键、早期和持久的事件。NAC治疗1个月后，氧化应激明显减弱，促炎细胞因子肿瘤坏死因子-α(TNF-α)及其受体TNF-R1R表达下调。这些数据表明，除了谷胱甘肽缺乏外，N-sMase的激活与心梗后CHF的进展有关，阻断N-sMase的激活参与了NAC治疗实现的脑梗塞后心力衰竭的恢复。心肌梗死后大鼠的NAC治疗是一种扰乱sTNFα/TNF-R1/N-sMase恶性循环的方法。(C)2007 Elsevier Inc.保留所有权利。
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-Ml rats. Biochemical studies at two time-points of NAC treatment, 3 days and I month, showed that inhibition of the neutral sphingomyclinase (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. (c) 2007 Elsevier Inc. All rights reserved.