Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis[S]

Journal of Lipid Research

卷:50

Chisato Ito-Ohsumi¹  Maki Tsujita¹  Sumiko Abe-Dohmae¹  Rui Lu¹  Chen-Ai Wu¹  Reijiro Arakawa¹  Noriyuki Iwamoto¹  Tomoji Aotsuka²  Hashime Kanazawa²  Kenji Shimizu²  Shinji Yokoyama³ 

[1] Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan;

[2] Nishi-Tokyo Research Center, Aska Pharmaceutical Co. Ltd., Hamura, Tokyo 205-8501, Japan;

[3] To whom correspondence should be addressed;

关键词: ATP binding cassette transporter A1;    high density lipoprotein;    atherosclerosis;    calpain;    probucol;   

DOI  :  

来源: DOAJ

【 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.

【 授权许可】

Unknown