HMG-CoA reductase inhibition and PPAR- alpha activation both inhibit cyclosporin A induced endothelin-1 secretion in cultured endothelial cells.
The use of cyclosporin A (CsA) in solid organ transplantation has been shown to be associated with the development of hypertension and nephrotoxicity. Several mechanisms, including endothelin (ET)-1-mediated systemic vasoconstriction, are considered to be responsible for CsA-induced hypertension. This study shows that: (i) incubation of CsA (1 microg) with bovine aortic endothelial cells leads to increased ET secretion by+40%; (ii) the use of compactin, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and fibric acid, the peroxisome-proliferator-activated receptor (PPAR)-alpha activator, inhibit the CsA-induced ET secretion to the level below the basal ET secretion, by -32% and -26% respectively; (iii) both inhibitions were reversed by the addition of mevalonate, suggesting communication between the HMG-CoA reductase product and PPAR-alpha pathway. The present findings may be of significant clinical relevance, since statins and fibrates beyond their hypolipidaemic action may represent a potential therapeutic tool in the treatment or prophylaxis of CsA-associated side effects. Furthermore, we suggest that the mevalonate metabolism would interfere with PPAR-alpha activity.
Kandoussi
Abdelmejid
A
Département de Recherches sur les Lipoprotéines et l'Athérosclérose, Inserm U545, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019, Lille, France.
Martin
François
F
Hazzan
Marc
M
Noël
Christian
C
Fruchart
Jean-Charles
JC
Staels
Bart
B
Duriez
Patrick
P
D000818:Animals; D001011:Aorta; D002417:Cattle; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016572:Cyclosporine / Q000009:adverse effects; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D058607:Fibric Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D019332:Endothelin-1; D058607:Fibric Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C012258:mevastatin; D002995:Clofibric Acid; D016572:Cyclosporine; D008148:Lovastatin; C019304:ciprofibrate; D008798:Mevalonic Acid