The antioxidant N-acetylcysteine prevents accelerated atherosclerosis in uremic apolipoprotein E knockout mice
The antioxidant N-acetylcysteine prevents accelerated atherosclerosis in uremic apolipoprotein E knockout mice
复制标题
DOI：
10.1111/j.1523-1755.2005.00332.x
复制
发表时间：
2005-06-01
影响因子：
19.6
通讯作者：
Massy, ZA
中科院分区：
文献类型：
--
作者：
Ivanovski, O;Szumilak, D;Massy, ZA
背景心血管疾病是慢性肾功能衰竭（CRF）患者最常见的死亡原因。因此，确定适当的治疗措施非常重要。抗氧化剂N-乙酰半胱氨酸（NAC）已被证明可以减少血液透析患者的心血管事件。在此，我们研究了NAC补充对载脂蛋白E缺陷（apoE（-/-））小鼠尿毒症增强的动脉粥样硬化的可能直接作用。在8周龄雌性apoE（-/-）小鼠中通过手术诱导尿毒症。在产生CRF后两周，将小鼠随机接受NAC（每天口服管饲200 mg/kg，持续8周）或安慰剂。将它们与接受安慰剂的假手术apoE（-/-）小鼠对照组进行比较。治疗8周后处死小鼠，测量主动脉根部和降主动脉粥样硬化斑块的横截面积。术后10周，尿毒症apoE（-/-）小鼠的动脉粥样硬化病变明显大于非尿毒症对照组。这种加速的动脉粥样硬化与主动脉硝基酪氨酸表达和胶原斑块含量的增加有关。与安慰剂治疗相比，NAC治疗可抑制动脉粥样硬化病变的进展和斑块胶原蛋白含量。此外，NAC治疗尿毒症动物的斑块显示硝基酪氨酸表达显著降低，而两个尿毒症组的巨噬细胞浸润程度相当。三组间平均动脉压无差异。我们首次表明，抗氧化剂NAC能够减少动脉粥样硬化的进展，在尿毒症增强动脉粥样硬化的动物模型，可能是通过减少氧化应激。
Background. Cardiovascular disease is the most frequent cause of mortality in chronic renal failure (CRF). Therefore, it is important to identify appropriate treatment measures. The antioxidant N-acetylcysteine (NAC) has been shown to reduce cardiovascular events in hemodialysis patients. Here we examine a possible direct effect of NAC supplementation on uremia-enhanced atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice.Methods. Uremia was induced surgically in 8-week-old female apoE(-/-) mice. Two weeks after creation of CRF mice were randomized to receive either NAC (daily oral gavage with 200 mg/kg for 8 weeks) or placebo. They were compared to a control group of sham-operated apoE(-/-) mice receiving placebo. After 8 weeks of treatment, the mice were sacrificed, and the cross-section surface area of atherosclerotic plaques was measured in aortic root and descending aorta.Results. At 10 weeks following surgery, atherosclerotic lesions were significantly larger in uremic apoE(-/-) mice than in nonuremic controls. This accelerated atherosclerosis was associated with an increase in aortic nitrotyrosine expression and collagen plaque content. NAC treatment inhibited the progression of atherosclerotic lesions and plaque collagen content compared with placebo treatment. In addition, plaques from NAC-treated uremic animals showed a significant decrease in nitrotyrosine expression whereas the degree of macrophage infiltration was comparable in both uremic groups. There was no difference in mean arterial blood pressure between the three groups.Conclusion. We show for the first time that the antioxidant NAC is capable of reducing atheroma progression, in an animal model of uremia-enhanced atherosclerosis, probably via a decrease in oxidative stress.