N-acetylcysteine reverses cardiac myocyte dysfunction in HIV-Tat proteinopathy
N-acetylcysteine reverses cardiac myocyte dysfunction in HIV-Tat proteinopathy
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DOI：
10.1152/japplphysiol.00068.2012
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发表时间：
2012-07-01
影响因子：
3.3
通讯作者：
Finkel, Mitchell S.
中科院分区：
文献类型：
--
作者：
Chen, Fangping;Lewis, William;Finkel, Mitchell S.
陈峰，刘建军，陈建军，陈建军。n -乙酰半胱氨酸逆转HIV-Tat蛋白病心肌细胞功能障碍。中国生物医学工程学报（英文版），2012；2012年5月3日首次发表；doi: 10.1152 / japplphysiol.00068.2012。-艾滋病毒心肌病在全世界约3300万艾滋病毒感染者中仍然非常普遍。在发展中国家尤其如此。HIV感染后心肌功能障碍的潜在机制包括HIV蛋白的直接作用。我们之前报道过心肌细胞特异性表达HIV-Tat （Tat）导致小鼠心肌病模型。我们现在报告答展览减少心肌ATP(野生型(WT)与乙转基因(TG), P < 0.01),肌细胞谷胱甘肽水平(WT与TG, P < 0.01),降低GSH / GSSG比率(WT与TG, P < 0.01),增加过氧化氢水平(WT与TG, P < 0.05),并增加过氧化氢酶(TG与WT, P < 0.05)和GPX1(谷胱甘肽过氧化物酶1)活动(WT与TG, P < 0.05),减弱心脏肌细胞积极inotropy(%峰值缩短,WT与TG, P < 0.01;+dl/dt, WT vs. TG, P < 0.01)和负性肌力（-dl/dt, WT vs. TG, P < 0.01）， Ca2+的肌力反应减弱（P < 0.01），体外解剖和功能生存时间缩短（P < 0.01）。巯基供体n -乙酰半胱氨酸（NAC; 10(-4) M）完全逆转了Tat的正性和负性肌力缺陷；GSH （P < 0.01）和GSH/GSSG （P < 0.01）升高；逆转H2O2水平（P < 0.05）和GPX1活性（P < 0.05）；对Ca2+的钝化肌力反应归一化（P < 0.01）。NAC (10(-7)) M归一化收缩功能持续时间从120 min开始（P < 0.01），对GSH和GSH/GSSG无影响。NAC （10(-4) M）逆转心肌细胞功能障碍和氧化应激标志物。NAC （10(-7) M）增强肌细胞功能，不依赖于谷胱甘肽的变化。阐明NAC对gsh依赖性和非gsh依赖性的有益作用的分子机制，将为人类心肌病发现新的心肌蛋白病变治疗靶点。
Chen F, Lewis W, Hollander JM, Baseler W, Finkel MS. N-acetylcysteine reverses cardiac myocyte dysfunction in HIV-Tat proteinopathy. J Appl Physiol 113: 105-113, 2012. First published May 3, 2012; doi:10.1152/japplphysiol.00068.2012.-HIV cardiomyopathy remains highly prevalent among the estimated 33 million HIV-infected individuals worldwide. This is particularly true in developing countries. Potential mechanisms responsible for myocardial dysfunction following HIV infection include direct effects of HIV proteins. We have previously reported that cardiac myocyte-specific expression of HIV-Tat (Tat) results in a murine cardiomyopathy model. We now report that Tat exhibits decreased myocardial ATP [wild type (WT) vs. Tat transgenic (TG), P < 0.01] and myocyte GSH levels (WT vs. TG, P < 0.01), decreased GSH/GSSG ratio (WT vs. TG, P < 0.01), increased H2O2 levels (WT vs. TG, P < 0.05), and increased catalase (TG vs. WT, P < 0.05) and GPX1 (glutathione peroxidase 1) activities (WT vs. TG, P < 0.05), blunted cardiac myocyte positive inotropy (% peak shortening, WT vs. TG, P < 0.01; +dl/dt, WT vs. TG, P < 0.01) and negative inotropy (-dl/dt, WT vs. TG, P < 0.01), and blunted inotropic responses to Ca2+ (P < 0.01, for each) and shortened anatomical and functional survival in vitro (P < 0.01). The sulfhydryl donor, N-acetylcysteine (NAC; 10(-4) M), completely reversed both the positive and negative inotropic defects in Tat; increased GSH (P < 0.01) and GSH/GSSG (P < 0.01); reversed H2O2 level (P < 0.05) and GPX1 activity (P < 0.05); and normalized the blunted inotropic response to Ca2+ (P < 0.01). NAC (10(-7)) M normalized duration of contractile function from 120 min (P < 0.01), with no effect on GSH and GSH/GSSG. NAC (10(-4) M) reverses cardiac myocyte dysfunction and markers of oxidative stress. NAC (10(-7) M) enhances myocyte function independent of changes in glutathione. Elucidating the molecular mechanisms involved in the GSH-dependent and GSH-independent salutary effects of NAC should identify novel therapeutic targets for myocardial proteinopathies recently appreciated in human cardiomyopathies.