Elevation of cyclic AMP by iloprost and prostaglandin E1 increases cholesterol efflux and the binding capacity for high-density lipoproteins in human fibroblasts.
Elevation of cAMP concurrently enhances cholesterol efflux and binding of HDL3 in human skin fibroblasts. These effects were observed regardless of the route by which cAMP levels were increased. Cholesterol efflux and HDL3 binding were stimulated by the cAMP analogue CPT-cAMP, the adenylate cyclase activator forskolin, and by iloprost and prostaglandin E1 (PGE1) (which elevate cAMP via receptor-mediated processes). Dideoxyforskolin and PGF2alpha, which do not elevate cAMP, altered neither cholesterol efflux nor binding of HDL3. Inhibition of protein kinase A with H89 abolished the stimulatory effects of CPT-cAMP and iloprost, suggesting protein kinase A involvement in enhancing cholesterol efflux and HDL3 binding. Enhancement of HDL3 binding by iloprost was due to increased maximal capacity of the cells to bind HDL3, i.e., a greater number of HDL3 binding sites. A positive correlation was demonstrated between changes in HDL3 binding and changes in [3H]cholesterol efflux. The data are compatible with a model in which cholesterol efflux is partially dependent upon HDL binding to the cells. A short exposure to iloprost was sufficient to stimulate cAMP synthesis, triggering a chain of events leading to increased HDL3 binding and [3H]cholesterol efflux 20-24 h later. We conclude that both cholesterol efflux and the maximal capacity for HDL3 binding are enhanced by elevation of cellular cAMP. Cyclic AMP-elevating prostanoids could initiate these responses in vivo.
Middleton
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A
School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Middleton
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B
D000527:Alprostadil / Q000494:pharmacology*; D001665:Binding Sites; D001693:Biological Transport, Active / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D015237:Dinoprost / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000378:metabolism*; D053440:Lipoproteins, HDL3
D008075:Lipoproteins, HDL; D053440:Lipoproteins, HDL3; D005576:Colforsin; D002784:Cholesterol; D015237:Dinoprost; D000242:Cyclic AMP; D000527:Alprostadil; D016285:Iloprost