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

Abstract
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 μg/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.
Conclusions—Low-dose proteasome inhibition exerts antioxidative and anti-inflammatory effects and attenuates development of atherosclerotic lesions in low-density lipoprotein receptor–deficient mice.
- Received November 4, 2011.
- Accepted April 5, 2012.
- © 2012 American Heart Association, Inc.
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- Attenuation of Early Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice by Proteasome InhibitionNicola Wilck, Mandy Fechner, Henryk Dreger, Bernd Hewing, Aimara Arias, Silke Meiners, Gert Baumann, Verena Stangl, Karl Stangl and Antje LudwigArteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.249342, originally published April 19, 2012https://doi.org/10.1161/ATVBAHA.112.249342
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- Attenuation of Early Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice by Proteasome InhibitionNicola Wilck, Mandy Fechner, Henryk Dreger, Bernd Hewing, Aimara Arias, Silke Meiners, Gert Baumann, Verena Stangl, Karl Stangl and Antje LudwigArteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.249342, originally published April 19, 2012https://doi.org/10.1161/ATVBAHA.112.249342