The effects of the statins lovastatin and cerivastatin on signalling by the prostanoid IP-receptor

1 The prostanoid-IP receptor may be unique among G protein coupled receptor s in that it is isoprenylated. In this study, we investigated the effects o f the statins lovastatin and cerivastatin on signalling by the mouse (m) IP and the human (h) IP receptors, over-expressed in human embryonic kidney ( HEK) 293 cells and by the hIP receptor, endogenously expressed in human ery throleukaemia cells. 2 Both statins significantly reduced IP receptor-mediated cyclic AMP genera tion and intracellular calcium ([Ca2+](i)) mobilization in a time and conce ntration dependent manner but had no effect on signalling by the non-isopre nylated beta (2) adrenergic receptor or by the human prostanoid-TP receptor isoforms. 3 Cerivastatin (IC50, 50-90 nM) was significantly more potent than lovastat in (IC50, 0.80-4.2 muM) in inhibiting IP receptor signalling. 4 Whereas IC50 values indicated that the hIP receptor was significantly mor e sensitive than the mIP receptor to the statins, the extent of inhibition of cyclic AMP generation by the mIP receptor was significantly greater than that of the hip receptor to either statin, even at the highest concentrati ons used. 5 Pretreatment with either statin significantly reduced IP receptor mediate d desensitization of signalling by the h.TP alpha, but not by the h.TP beta , receptor isoform. 6 These data generated in whole cells point to the possibility that statin therapy may interfere with IP receptor signalling in vivo; such interferenc e may be extenuated under conditions where circulating statin levels are el evated and may account, in part, for some of the pleiotropic affects of the statins not attributed solely to their lipid lowering properties.