title: Divergent action of calcium channel blockers on ATP-binding cassette protein expression.
abstract: Calcium channel blockers (CCBs) are widely used in clinical practice, and have been reported to be effective in preventing the progression of atherosclerosis. We examined whether various types of calcium channel blockers affected the expression of ATP binding cassette transporter A1 (ABCA1), a factor contributing to anti-atherogenesis. Undifferentiated monocytic cell line, THP-1 cells were maintained in RPMI 1640 medium and treated with different kinds of calcium channel blockers. Among the calcium channel blockers tested, aranidipine and efonidipine increased ABCA1 protein expression without an increase in ABCA1 mRNA expression, whereas other calcium channel blockers (eg, nifedipine, amlodipine, and nicardipine) or T-type calcium channel blockers (eg, mibefradil and nickel chloride) failed to upregulate ABCA1 expression. H89, a protein kinase A inhibitor inhibited the aranidipine-induced ABCA1 protein expression, whereas genistein (a tyrosine kinase inhibitor), or AG490 (a JAK-2 inhibitor) had no effects. Neither of these inhibitors suppressed the efonidipine-induced ABCA1 protein expression. Intracellular cAMP levels were elevated only by aranidipine, but not by efonidipine. In conclusion, aranidipine and efonidipine have the ability to induce ABCA1 protein by distinct mechanisms; protein kinase A is involved in the aranidipine-induced ABCA1 upregulation. This non-class effect of calcium channel blockers may potentially offer beneficial action in the treatment of hypertensive subjects with atherosclerosis.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Shinanomachi, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanda
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Satoru
authors.initials: S
authors.lastname: Tatematsu
authors.forename: Koichiro
authors.initials: K
authors.lastname: Homma
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takamatsu
authors.forename: Naoki
authors.initials: N
authors.lastname: Sugano
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000235:genetics*; D050197:Atherosclerosis / Q000517:prevention & control; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004095:Dihydropyridines / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D053614:Janus Kinase 2; D009596:Nitrophenols / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C066425:efonidipine; C059427:aranidipine; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D017868:Cyclic AMP-Dependent Protein Kinases