title: 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.
  
  
  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.
authors.affiliation: Medizinische Klinik für Kardiologie und Angiologie, Charité-Universitätsmedizin Berlin Campus Mitte, Charitéplatz 1, D-10117 Berlin, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Wilck
authors.forename: Mandy
authors.initials: M
authors.lastname: Fechner
authors.forename: Henryk
authors.initials: H
authors.lastname: Dreger
authors.forename: Bernd
authors.initials: B
authors.lastname: Hewing
authors.forename: Aimara
authors.initials: A
authors.lastname: Arias
authors.forename: Silke
authors.initials: S
authors.lastname: Meiners
authors.forename: Gert
authors.initials: G
authors.lastname: Baumann
authors.forename: Verena
authors.initials: V
authors.lastname: Stangl
authors.forename: Karl
authors.initials: K
authors.lastname: Stangl
authors.forename: Antje
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001897:Boronic Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069286:Bortezomib; D018932:Chemokine CCL2 / Q000097:blood; D002784:Cholesterol / Q000097:blood; D019295:Computational Biology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000097:blood; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001897:Boronic Acids; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D015850:Interleukin-6; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011973:Receptors, LDL; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D013481:Superoxides; D000069286:Bortezomib; D002784:Cholesterol; D046988:Proteasome Endopeptidase Complex