Open AccessAttenuation of Early Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice by Proteasome Inhibition
Author(s) -
Nicola Wilck,
Mandy Fechner,
Henryk Dreger,
Bernd Hewing,
Aimara Arias,
Silke Meiners,
Gert Baumann,
Verena Stangl,
Karl Stangl,
Antje Ludwig
Publication year - 2012
Publication title -
arteriosclerosis, thrombosis, and vascular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.007
H-Index - 270
eISSN - 1524-4636
pISSN - 1079-5642
DOI - 10.1161/atvbaha.112.249342
Subject(s) - bortezomib , proteasome inhibitor , chemistry , endocrinology , lipoprotein , ldl receptor , receptor , medicine , foam cell , monocyte , low density lipoprotein , pharmacology , proteasome , cholesterol , biochemistry , multiple myeloma
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. Conclusion— Low-dose proteasome inhibition exerts antioxidative and anti-inflammatory effects and attenuates development of atherosclerotic lesions in low-density lipoprotein receptor–deficient mice.