RRC ID |
6611
|
Author |
Arakawa R, Tsujita M, Iwamoto N, Ito-Ohsumi C, Lu R, Wu CA, Shimizu K, Aotsuka T, Kanazawa H, Abe-Dohmae S, Yokoyama S.
|
Title |
Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis.
|
Journal |
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.
|
Volume |
50(11)
|
Pages |
2299-305
|
Published |
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
|
Times Cited |
35
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
Resource |
Human and Animal Cells |
|