文章基本信息

标题：Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis
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作者：Reijiro Arakawa ; Maki Tsujita ; Noriyuki Iwamoto 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2009
卷号：50
期号：11
页码：2299-2305
DOI：10.1194/jlr.M900122-JLR200
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Expression of ABCA1 is regulated by transcription of the gene and calpain-mediated proteolytic degradation, and inhibition ABCA1 degradation results in increased ABCA1 and HDL biogenesis in vitro. We examined whether this approach could be a potential antiatherogenic treatment. Although probucol inhibits both the activity and degradation of ABCA1, its oxidized products, spiroquinone and diphenoquinone, reduce degradation of ABCA1 without inhibiting its activity or altering transcription of the ABCA1 gene. Accordingly, both compounds enhanced apolipoprotein A-I/ABCA1-dependent generation of HDL in vitro, and increased hepatic ABCA1 and plasma HDL without increasing antioxidant activity in plasma when given to rabbits. Both compounds also decreased vascular lipid deposition in cholesterol-fed rabbits. We therefore conclude that stabilization of ABCA1 against calpain-mediated degradation is a novel and potentially important strategy to increase HDL formation and prevent atherosclerosis. Spiroquinone and diphenoquinone are potential seeds for development of such drugs.
关键词：ATP binding cassette transporter A1 ; high density lipoprotein ; atherosclerosis ; calpain ; probucol