Nontoxic proteasome inhibition activates a protective antioxidant defense response in endothelial cells.
Inhibitors of the ubiquitin-proteasome system offer a new and promising approach in the therapy of proliferative and inflammatory diseases. In order to narrow the therapeutic window for cytotoxic effects on the one hand and nontoxic, anti-inflammatory effects on the other hand, we elucidated the complex cellular effects of toxic versus nontoxic proteasome inhibition in human endothelial cells by expressional profiling. Nontoxic doses of proteasome inhibitors induced a defined, dose-dependent transcriptional response that was markedly attenuated in terms of gene number and amplitude of regulation compared to toxic doses. In particular, we observed uniform upregulation of several antioxidative enzymes and differential regulation of genes involved in endothelial function. This adaptive transcriptional pattern was translated into a protective response of endothelial cells against H(2)O(2)-induced oxidative stress and into improvement of endothelial function of rat aortic rings. Our data thus suggest that nontoxic proteasome inhibition might offer a new therapeutic approach for the treatment of endothelial dysfunction in cardiovascular disorders.
Meiners
Silke
S
Universitätsmedizin Berlin, Charité, Medizinische Klinik und Poliklinik mit Schwerpunkt Kardiologie, Angiologie, Pneumologie, Schumannstrasse 20/21, D - 10117 Berlin, Germany.
Ludwig
Antje
A
Lorenz
Mario
M
Dreger
Henryk
H
Baumann
Gert
G
Stangl
Verena
V
Stangl
Karl
K
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology / Q000633:toxicity; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D019610:Cytoprotection / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007976:Leupeptins / Q000494:pharmacology / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D061988:Proteasome Inhibitors; D014158:Transcription, Genetic / Q000187:drug effects
D000975:Antioxidants; D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C423917:MG 262; D061988:Proteasome Inhibitors; D006861:Hydrogen Peroxide; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde