Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
J Atheroscler Thromb. 2011;18(11):998-1008. doi: 10.5551/jat.8870. Epub 2011 Aug 27.
N-acetylcysteine (NAC) has antioxidant and anti-inflammatory properties. To explore the mechanisms underlying atherosclerotic plaque stabilization induced by NAC, we examined the effects of NAC administration in apoE-deficient mice on the expression of the receptor of advanced glycation end products (RAGE), matrix metalloproteinases (MMPs) and the activation of nuclear factor kappa B (NF-κB) in atherosclerotic plaques.
10-week-old ApoE(-/-) mice fed with atherogenic diet were treated with NAC (200 mg/kg/ day) for 8 weeks. Serum lipid, glucose and malondialdehyde (MDA) were detected. The size and composition of atherosclerotic plaques were measured by en face analysis, Movat staining, immunofluorescence and immunohistochemistry, respectively. Reactive oxygen species (ROS) generation in aortic root was tested by DHE staining. The levels of vascular cell adhesion molecule-1(VCAM-1), NF-κB, phosphor-NF-κB, I-κB, phosphor-I-κB, RAGE, MMP2 and MMP9 in descending arteries were analyzed by Western blot.
ApoE(-/-) mice administrated with NAC displayed reduced serum MDA level and impaired ROS generation in aortic root. However, NAC did not affect the levels of plasma glucose, lipids and the size of atherosclerotic lesions. Analysis of plaque composition showed decreased amounts of macrophages, lipid deposition, but not smooth muscle cells, and increased collagen content in atherosclerotic lesions in apoE(-/-) mice administered with NAC. Moreover, we found that NAC down-regulated the expression of VCAM-1, MMP2 and MMP9, accompanied by inhibition of NF-κB activation and reduced expression of RAGE.
In the present study, we show novel data to suggest that NAC promotes atherosclerotic plaque stabilization through suppression of RAGE, MMPs and NF-κB in apoE(-/-) mice.
N-乙酰半胱氨酸（NAC）具有抗氧化和抗炎作用。为了探索 NAC 诱导动脉粥样硬化斑块稳定化的机制，我们研究了 NAC 给药对载脂蛋白 E 缺陷（ApoE(-/-)）小鼠动脉粥样硬化斑块中晚期糖基化终产物受体（RAGE）、基质金属蛋白酶（MMPs）表达和核因子 kappa B（NF-κB）激活的影响。
10 周龄的 ApoE(-/-)小鼠喂食致动脉粥样硬化饮食，给予 NAC（200mg/kg/天）治疗 8 周。检测血清脂质、葡萄糖和丙二醛（MDA）。通过酶联免疫吸附试验（ELISA）、Movat 染色、免疫荧光和免疫组化分别检测动脉粥样硬化斑块的大小和成分。通过 DHE 染色检测主动脉根部活性氧（ROS）的产生。通过 Western blot 分析降主动脉中血管细胞间黏附分子-1（VCAM-1）、NF-κB、磷酸化 NF-κB、I-κB、磷酸化 I-κB、RAGE、MMP2 和 MMP9 的水平。
给予 NAC 的 ApoE(-/-)小鼠显示血清 MDA 水平降低，主动脉根部 ROS 生成受损。然而，NAC 并不影响血浆葡萄糖、脂质水平和动脉粥样硬化病变的大小。斑块成分分析显示，给予 NAC 的 ApoE(-/-)小鼠的动脉粥样硬化病变中巨噬细胞数量减少、脂质沉积减少、但平滑肌细胞数量无变化，胶原含量增加。此外，我们发现 NAC 下调 VCAM-1、MMP2 和 MMP9 的表达，同时抑制 NF-κB 激活和 RAGE 的表达。
本研究表明，NAC 通过抑制 ApoE(-/-)小鼠的 RAGE、MMPs 和 NF-κB 促进动脉粥样硬化斑块稳定化。
