Elevation of cyclic AMP by iloprost and prostaglandin E1 increases cholesterol efflux and the binding capacity for high-density lipoproteins in human fibroblasts

Abstract Elevation of cAMP concurrently enhances cholesterol efflux and binding of HDL 3 in human skin fibroblasts. These effects were observed regardless of the route by which cAMP levels were increased. Cholesterol efflux and HDL 3 binding were stimulated by the cAMP analogue CPT–cAMP, the adenylate cyclase activator forskolin, and by iloprost and prostaglandin E 1 (PGE 1 ) (which elevate cAMP via receptor-mediated processes). Dideoxyforskolin and PGF 2 α , which do not elevate cAMP, altered neither cholesterol efflux nor binding of HDL 3 . 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 HDL 3 binding. Enhancement of HDL 3 binding by iloprost was due to increased maximal capacity of the cells to bind HDL 3 , i.e., a greater number of HDL 3 binding sites. A positive correlation was demonstrated between changes in HDL 3 binding and changes in [ 3 H]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 HDL 3 binding and [ 3 H]cholesterol efflux 20–24 h later. We conclude that both cholesterol efflux and the maximal capacity for HDL 3 binding are enhanced by elevation of cellular cAMP. Cyclic AMP-elevating prostanoids could initiate these responses in vivo.