論文 - 詳細
| RRC ID | 6611 |
|---|---|
| 著者 | Arakawa R, Tsujita M, Iwamoto N, Ito-Ohsumi C, Lu R, Wu CA, Shimizu K, Aotsuka T, Kanazawa H, Abe-Dohmae S, Yokoyama S. |
| タイトル | Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis. |
| ジャーナル | J Lipid Res |
| Abstract |
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. |
| 巻・号 | 50(11) |
| ページ | 2299-305 |
| 公開日 | 2009-11-1 |
| DOI | 10.1194/jlr.M900122-JLR200 |
| PII | S0022-2275(20)30696-9 |
| PMID | 19458386 |
| PMC | PMC2759836 |
| MeSH | ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters / antagonists & inhibitors* ATP-Binding Cassette Transporters / genetics ATP-Binding Cassette Transporters / metabolism Animals Anticholesteremic Agents / pharmacology Antioxidants / metabolism Apolipoprotein A-I / metabolism Atherosclerosis / blood Atherosclerosis / metabolism Atherosclerosis / prevention & control* BALB 3T3 Cells Blotting, Western Calpain / metabolism Cell Line Cholesterol, HDL / blood Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism Humans Lipoproteins, HDL / biosynthesis* Lipoproteins, HDL / blood Macrophages / cytology Macrophages / drug effects Macrophages / metabolism Male Mice Microscopy, Confocal Probucol / pharmacology Quinones / pharmacology Rabbits Reverse Transcriptase Polymerase Chain Reaction Transfection |
| IF | 4.483 |
| 引用数 | 35 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | |