Verapamil increases the apolipoprotein-mediated release of cellular cholesterol by induction of ABCA1 expression via Liver X receptor-independent mechanism.
OBJECTIVE
Release of cellular cholesterol and phospholipid mediated by helical apolipoprotein and ATP-binding cassette transporter (ABC) A1 is a major source of plasma HDL. We investigated the effect of calcium channel blockers on this reaction.


RESULTS
Expression of ABCA1, apoA-I-mediated cellular lipid release, and HDL production were enhanced in cAMP analogue-treated RAW264 cells by verapamil, and similar effects were also observed with other calcium channel blockers. The verapamil treatment resulted in rapid increase in ABCA1 protein and its mRNA, but not the ABCG1 mRNA, another target gene product of the nuclear receptor liver X receptor (LXR). By using the cells transfected with a mouse ABCA1 promoter-luciferase construct (-1238 to +57bp), verapamil was shown to enhance the transcriptional activity. However, it did not increase transcription of LXR response element-driven luciferase vector.


CONCLUSIONS
The data demonstrated that verapamil increases ABCA1 expression through LXR-independent mechanism and thereby increases apoA-I-mediated cellular lipid release and production of HDL.
Suzuki
Shogo
S
Department of Biochemistry, Cell Biology, and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Nishimaki-Mogami
Tomoko
T
Tamehiro
Norimasa
N
Inoue
Kazuhide
K
Arakawa
Reijiro
R
Abe-Dohmae
Sumiko
S
Tanaka
Arowu R
AR
Ueda
Kazumitsu
K
Yokoyama
Shinji
S
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology; D003994:Bucladesine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008074:Lipoproteins / Q000235:genetics; D008075:Lipoproteins, HDL / Q000096:biosynthesis / Q000235:genetics; D000071518:Liver X Receptors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009529:Nicardipine / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D057093:Orphan Nuclear Receptors; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D014162:Transfection; D014700:Verapamil / Q000737:chemistry / Q000494:pharmacology*; D047392:beta-Cyclodextrins / Q000494:pharmacology
C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D002121:Calcium Channel Blockers; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D047392:beta-Cyclodextrins; C003585:22-hydroxycholesterol; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C012258:mevastatin; D003994:Bucladesine; D002784:Cholesterol; D008148:Lovastatin; D014700:Verapamil; D009529:Nicardipine; D009543:Nifedipine