Proteasome inhibition prevents experimentally-induced endothelial dysfunction

Aims: 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. Main methods: Endothelial dysfunction in isolated rat aortic rings was induced by incubation of rings with TNF alpha 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. Key findings: Incubation of rat aortic rings with TNF alpha for 48 h led to significant dose-dependent reduction of acetylcholine-induced vasorelaxation. Co-incubation with TNF alpha and the proteasome inhibitor MG132 resulted in dose-dependent improvement of endothelium-dependent vasorelaxation in comparison to rings treated with TNF alpha 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 SODI expression. Superoxide production was reduced in rings incubated with MG132 in comparison to controls. TNF alpha-induced upregulation of the potent vasoconstrictor endothelin was abolished by MG132. Significance: Proteasome inhibition prevents TNFa-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. (C) 2009 Elsevier Inc. All rights reserved.