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The antioxidant N-acetylcysteine promotes atherosclerotic plaque stabilization through suppression of RAGE, MMPs and NF-κB in ApoE-deficient mice.

AIMS
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.


METHODS
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.


RESULTS
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.


CONCLUSION
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.