title: Potent anti-inflammatory effects of low-dose proteasome inhibition in the vascular system.
abstract: Proteasome inhibitors are considered to have anti-inflammatory therapeutic potential. However, recent reports addressing proteasome inhibition in the vascular system are controversial, ranging from beneficial anti-inflammatory and anti-oxidative effects to potentiation of inflammation and oxidative stress. This study was based on the hypothesis that the divergent effects might be a result of a differential and dose-dependent responsiveness of vascular cells to proteasome inhibitors. We tested whether low doses of proteasome inhibitors would favor anti-inflammatory effects in vascular cells in vitro and in vivo. Human umbilical vein endothelial cells (HUVEC) were preincubated with proteasome inhibitors MG132 and MG262 at concentrations that did not affect cell viability during a 24-h treatment. Upon addition of tumor necrosis factor alpha (TNF-alpha) the induced expression of adhesion molecules and the adhesion of monocytic THP-1 cells to HUVECs was significantly lowered. However, nuclear translocation of NF-kappaB was only slightly diminished. Low-dose pretreatment with proteasome inhibitors decreased TNF-alpha-induced generation of reactive oxygen species in HUVEC. Bortezomib was administered at a dose of 50 microg/kg body weight to Dahl salt-sensitive rats (DSSR) on high-salt diet. This low-dose proteasome inhibition led to decreased hypertension-induced oxidative stress and reduced expression of vascular cell adhesion molecule 1 (VCAM-1) in the aortae.
authors.affiliation: Klinik für Kardiologie und Angiologie, Charité--Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Ludwig
authors.forename: Mandy
authors.initials: M
authors.lastname: Fechner
authors.forename: Nicola
authors.initials: N
authors.lastname: Wilck
authors.forename: Silke
authors.initials: S
authors.lastname: Meiners
authors.forename: Nicole
authors.initials: N
authors.lastname: Grimbo
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
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D001897:Boronic Acids; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D007976:Leupeptins; C423917:MG 262; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000069286:Bortezomib; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde