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J Atheroscler Thromb. 2011;18(3):209-16. Epub 2010 Nov 19.

Loss of clusterin limits atherosclerosis in apolipoprotein E-deficient mice via reduced expression of Egr-1 and TNF-α.

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  • 1Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan.

Abstract

AIM:

Whether clusterin/apolipoprotein J is antiatherogenic or proatherogenic is controversial. We reported that clusterin was markedly induced in media and neointima after vascular injury and that reduced clusterin expression reduced the proliferation of vascular smooth muscle cells (VSMCs), which induced G1 arrest via p53 and p21. The purpose of this study was to investigate the physiological function of clusterin in atherosclerosis using double-knockout mice (D-KO) of apolipoprotein E-deficient mice (apoE-KO) and clusterin-deficient mice (CLU-KO).

METHODS AND RESULTS:

Atherosclerotic lesions in the aortic root were quantitated at 20 weeks of age. Atherosclerotic lesions of D-KO were significantly smaller than those of apoE-KO (D-KO: 0.176±0.078 mm(2) vs. apoE-KO: 0.365±0.164 mm(2), p< 0.001). To identify underlying atherosclerotic mechanisms that were blocked by loss of clusterin, we performed immunohistochemical analysis of Egr-1. Egr-1 immunoreactivity in the nuclei of VSMCs in atherosclerotic lesions of apoE-KO was upregulated, whereas it was not in D-KO lesions. Western blotting demonstrated that the expression levels of Egr-1 and TNF-α in the D-KO were significantly lower than those in the apoE-KO. When VSMCs and macrophages were obtained from D-KO and apoE-KO, Western blotting showed that the expression levels of Egr-1 and TNF-α in VSMCs and macrophages of D-KO were significantly lower than those of apoE-KO.

CONCLUSION:

Loss of clusterin strongly suppressed apoE-KO-induced atherosclerotic lesions at a step prior to the expression of Egr-1 and TNF-α, suggesting that clusterin is a candidate for an antiatherogenic target.

PMID:
21099169
[PubMed - indexed for MEDLINE]
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