Verapamil Increases the Apolipoprotein-Mediated Release of Cellular Cholesterol by Induction of ABCA1 Expression Via Liver X Receptor-Independent Mechanism

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 24; no. 3; pp. 519 - 525
• Main Authors: Suzuki, Shogo, Nishimaki-Mogami, Tomoko, Tamehiro, Norimasa, Inoue, Kazuhide, Arakawa, Reijiro, Abe-Dohmae, Sumiko, Tanaka, Arowu R, Ueda, Kazumitsu, Yokoyama, Shinji
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.03.2004; Hagerstown, MD Lippincott
• Subjects: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Apolipoprotein A-I - physiology; Atherosclerosis (general aspects, experimental research); ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP-Binding Cassette Transporters - biosynthesis; ATP-Binding Cassette Transporters - genetics; beta-Cyclodextrins - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Bucladesine - pharmacology; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Cardiology. Vascular system; Cell Line - drug effects; Cell Line - metabolism; Cholesterol - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; DNA-Binding Proteins; Gene Expression Regulation - drug effects; Genes, Reporter; Humans; Hydroxycholesterols - pharmacology; Lipoproteins - genetics; Lipoproteins, HDL - biosynthesis; Lipoproteins, HDL - genetics; Liver X Receptors; Lovastatin - analogs & derivatives; Lovastatin - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Mice; Nicardipine - pharmacology; Nifedipine - pharmacology; Orphan Nuclear Receptors; Phospholipids - metabolism; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; RNA, Messenger - biosynthesis; Stereoisomerism; Transfection; Verapamil - chemistry; Verapamil - pharmacology; ABCA; Digestive system; Liver; Calcium antagonist; Lipids; Cardiovascular disease; Apolipoprotein; Cholesterol; Vascular disease; HDL; calcium channel blocker; Atherosclerosis; Verapamil; Lipoprotein HDL; Macrophage
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000117178.94087.ba

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. METHODS AND 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.