Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis.
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.
Arakawa
Reijiro
R
Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Tsujita
Maki
M
Iwamoto
Noriyuki
N
Ito-Ohsumi
Chisato
C
Lu
Rui
R
Wu
Chen-Ai
CA
Shimizu
Kenji
K
Aotsuka
Tomoji
T
Kanazawa
Hashime
H
Abe-Dohmae
Sumiko
S
Yokoyama
Shinji
S
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D041702:BALB 3T3 Cells; D015153:Blotting, Western; D002154:Calpain / Q000378:metabolism; D002460:Cell Line; D008076:Cholesterol, HDL / Q000097:blood; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000096:biosynthesis* / Q000097:blood; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D011341:Probucol / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D000975:Antioxidants; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D011809:Quinones; D049452:Green Fluorescent Proteins; C001081:diphenoquinone; D002154:Calpain; D011341:Probucol