Proteasome inhibition prevents experimentally-induced endothelial dysfunction.
OBJECTIVE
We recently demonstrated that non-toxic inhibition of the proteasome upregulates antioxidative enzymes and leads to an adaptive transcriptional pattern in endothelial cells. We therefore hypothesized that proteasome inhibition could prevent experimentally-induced endothelial dysfunction. As there are conflicting data about the effects of proteasome inhibition on endothelial function, we investigated whether proteasome inhibition could prevent experimentally-induced endothelial dysfunction.


METHODS
Endothelial dysfunction in isolated rat aortic rings was induced by incubation of rings with TNFalpha for 48 h. To study the effects of the inhibition of the proteasome, selected rings were co-treated with proteasome inhibitors. Vasorelaxation and expression of genes involved in endothelial function were evaluated.


RESULTS
Incubation of rat aortic rings with TNFalpha for 48 h led to significant dose-dependent reduction of acetylcholine-induced vasorelaxation. Co-incubation with TNFalpha and the proteasome inhibitor MG132 resulted in dose-dependent improvement of endothelium-dependent vasorelaxation in comparison to rings treated with TNFalpha alone. Levels of eNOS mRNA and protein were reduced despite improved vascular function after treatment with MG132. MG132 markedly suppressed mRNA levels of NADPH oxidase subunits and increased SOD1 expression. Superoxide production was reduced in rings incubated with MG132 in comparison to controls. TNFalpha-induced upregulation of the potent vasoconstrictor endothelin was abolished by MG132.


CONCLUSIONS
Proteasome inhibition prevents TNFalpha-induced vascular dysfunction by reduction of superoxide production and suppression of endothelin levels. The balance between vasoconstriction and vasodilatation is shifted in favour of endothelium-dependent vasodilation.
Lorenz
Mario
M
Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charité-Universitätsmedizin Berlin, Germany.
Wilck
Nicola
N
Meiners
Silke
S
Ludwig
Antje
A
Baumann
Gert
G
Stangl
Karl
K
Stangl
Verena
V
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha; D014652:Vascular Diseases / Q000139:chemically induced; D014664:Vasodilation / Q000187:drug effects
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D052250:Nitric Oxide Synthase Type III