on January 15, 2004
Published online before print January 15, 2004, doi: 10.1161/01.ATV.0000117178.94087.ba
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Submitted on August 26, 2003
Accepted on December 15, 2003
Verapamil Increases the Apolipoprotein-Mediated Release of Cellular Cholesterol by Induction of ABCA1 Expression Via Liver X Receptor-Independent Mechanism
Shogo Suzuki ;
From the Department of Biochemistry, Cell Biology, and Metabolism (S.S., R.A., S.A.-D., S.Y.), Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, Japan; the Department of Biochemistry and Metabolism (T.N.-M.., N.T., K.I.), National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan; and the Laboratory of Cellular Biochemistry (A.R.T., K.U.), Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
* To whom correspondence should be addressed. E-mail: syokoyam{at}med.nagoya-cu.ac.jp.
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.
Key words: calcium channel blocker • verapamil • ABCA1 • HDL • cholesterol • apolipoprotein • macrophage
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