Anti-atherogenic antioxidants regulate the expression and function of proteasome alpha-type subunits in human endothelial cells.
It has been proposed that phenolic antioxidants such as probucol exert their anti-atherogenic effects through scavenging lipid-derived radicals. In this study the potential for genomics to reveal unanticipated pharmacological properties of phenolic antioxidants is explored. It was found that two anti-atherogenic compounds, BO-653 and probucol, inhibited the expression of three alpha-type proteasome subunits, PMSA2, PMSA3, and PMSA4 in human umbilical vein endothelial cells. Here we report that both BO-653 and probucol caused not only inhibition of the mRNA levels of these three subunits but also inhibition of both the gene expression and protein synthesis of the alpha-type subunit, PMSA1. Other subunit components of the proteasome such as the beta-type subunits (PMSB1, PMSB7), the ATPase subunit of 19 S (PMSC6), the non-ATPase subunit of 19 S (PMSD1), and PA28 (PMSE2) were not significantly affected by treatment with these compounds. The specific inhibition of alpha-type subunit expression in response to these antioxidants resulted in functional alterations of the proteasome with suppression of degradation of multiubiquitinated proteins and IkappaBalpha. These results suggest that certain compounds previously classified solely as antioxidants are able to exert potentially important modulatory effects on proteasome function.
Takabe
W
W
Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904, Japan.
Kodama
T
T
Hamakubo
T
T
Tanaka
K
K
Suzuki
T
T
Aburatani
H
H
Matsukawa
N
N
Noguchi
N
N
D000975:Antioxidants / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000235:genetics; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism
D000975:Antioxidants; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex