Attenuation of Early Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice by Proteasome Inhibition

作者：Wilck Nicola; Fechner Mandy; Dreger Henryk; Hewing Bernd; Arias Aimara; Meiners Silke; Baumann Gert; Stangl Verena; Stangl Karl^*; Ludwig Antje

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2012, 32(6): 1418-+.

DOI：10.1161/ATVBAHA.112.249342

• atherosclerosis
• inflammation
• oxidative stress
• proteasome

Objective-Low and nontoxic proteasome inhibition has anti-inflammatory, antiproliferative, and antioxidative effects on vascular cells in vitro and in vivo. We hypothesized that low-dose inhibition of the proteasome could provide antiatherogenic protection. The present study investigated the effect of low-dose proteasome inhibition on early lesion formation in low-density lipoprotein receptor-deficient mice fed a Western-type diet.
Methods and Results-Male low-density lipoprotein receptor-deficient mice, 10 weeks old, were fed a Western-type diet for 6 weeks with intraperitoneal injections of bortezomib or solvent. Bortezomib was injected at a dose of 50 mu g/kg body weight. Cholesterol plasma levels were not affected by bortezomib treatment. En face Oil Red O staining of aortae and aortic root cryosections demonstrated significant reduction of atherosclerotic lesion coverage in bortezomib-treated animals. Bortezomib significantly reduced vascular cellular adhesion molecule-1 expression and macrophage infiltration as shown by histological analysis. Bortezomib treatment resulted in a significant reduction of superoxide content, lipid peroxidation and protein oxidation products, serum levels of monocyte chemoattractant protein-1, and interleukin-6. Gene expression microarray analysis showed that expressional changes induced by Western-type diet were attenuated by treatment with low-dose bortezomib.
Conclusion-Low-dose proteasome inhibition exerts antioxidative and anti-inflammatory effects and attenuates development of atherosclerotic lesions in low-density lipoprotein receptor-deficient mice. (Arterioscler Thromb Vasc Biol. 2012;32:1418-1426.)

• 出版日期2012-6