Effect of the statin atorvastatin on intracellular signalling by the prostacyclin receptor in vitro and in vivo.
Prostacyclin plays a central role within the vasculature. We have previously established that the prostacyclin receptor (IP) undergoes isoprenylation, a lipid modification obligate for its function. The aim of the current study was to investigate the effect of the hydroxy methyl glutaryl co-enzyme A reductase inhibitor atorvastatin on signalling and function of the IP expressed in mammalian whole cells and in platelets isolated from patients undergoing therapeutic intervention with atorvastatin. Initially, the effect of atorvastatin on signalling by the human (h) and mouse (m) IP overexpressed in human embryonic kidney 293 cells and the hIP endogenously expressed in human erythroleukaemic 92.1.7 cells was investigated. Atorvastatin significantly reduced IP-mediated cAMP generation (IC(50) 6.6-11.1 microm) and [Ca(2+)](i) mobilization (IC(50) 7.2-16.4 microm) in a concentration-dependent manner, but had no effect on signalling by the nonisoprenylated beta(2) adrenergic receptor or the alpha or beta isoforms of the human thromboxane A(2) receptor (TP). Moreover, atorvastatin significantly reduced IP-mediated crossdesensitization of signalling by TP alpha (IC(50) 10.4 microm), but not by TP beta. In contrast to the whole-cell data, atorvastatin therapy did not interfere with IP-mediated cAMP generation or IP-induced inhibition of TP-mediated aggregation of platelets isolated from human volunteers undergoing therapeutic intervention with atorvastatin (10-80 mg per daily dose). In conclusion, while data generated in whole cells indicated that atorvastatin significantly impairs signalling by both the hIP and mP, the in vivo clinical data indicated that, at the administered therapeutic dose, atorvastatin does not significantly compromise IP signalling and function in humans.
Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Sarah J
SJ
O'Meara
B Therese
BT
Kinsella
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood / Q000145:classification; D002986:Clinical Trials as Topic; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005231:Fatty Acids, Unsaturated; D005260:Female; D006538:Heptanoic Acids / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D016285:Iloprost / Q000494:pharmacology; D007494:Ireland; D008055:Lipids / Q000097:blood / Q000145:classification; D008297:Male; D051379:Mice; D008875:Middle Aged; D011412:Propanolamines / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D011758:Pyrroles / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay / Q000379:methods; D020239:Receptor Cross-Talk / Q000187:drug effects; D044006:Receptors, Epoprostenol; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014316:Tritium
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006538:Heptanoic Acids; D006827:Hydantoins; D006834:Hydrazines; D008055:Lipids; C113936:PTGIR protein, human; D011412:Propanolamines; C491910:Ptgir protein, mouse; D011758:Pyrroles; D044006:Receptors, Epoprostenol; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D014316:Tritium; C030669:BW 245C; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D002784:Cholesterol; D000069059:Atorvastatin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D016285:Iloprost; C033394:CGP 12177; D002118:Calcium; C036293:prostaglandin D2 receptor