Cyclic AMP-specific phosphodiesterase 4 inhibitors promote ABCA1 expression and cholesterol efflux.
ATP cassette binding protein 1 (ABCA1) controls the apolipoprotein-mediated cholesterol efflux pathway and determines plasma HDL levels. Although cAMP is known to promote ABCA1 expression and cholesterol efflux from cells, it has not been determined whether cyclic nucleotide phosphodiesterase (PDE) isoforms regulate this pathway. We show that rolipram and cilomilast, inhibitors of cAMP-specific PDE4, increase apolipoprotein A-I (apoA-I)-mediated cholesterol efflux up to 80 and 140% in human THP-1 and mouse J774.A1 macrophages, respectively, concomitant with an elevation of cAMP levels. The EC(50) value was estimated to be 1 to 2 microM for both inhibitors. Rolipram and cilomilast also increase ABCA1 protein expression in THP-1 and J774.A1 macrophages. Thus, PDE4 inhibitors cause parallel increases in cAMP levels, ABCA1 expression and apoA-I-mediated cholesterol efflux. PDE4 inhibitors may provide a novel strategy for the treatment of cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions.
Lin
Guorong
G
Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195-7470, USA.
Bornfeldt
Karin E
KE
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001993:Bronchodilator Agents / Q000494:pharmacology; D002264:Carboxylic Acids; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020889:Rolipram / Q000494:pharmacology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001993:Bronchodilator Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; C433247:Cilomilast; D002784:Cholesterol; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram