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 (1µM) 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.
HMG-CoA reductase inhibition and PPAR-alpha activation both inhibit cyclosporin A induced endothelin-1 secretion in cultured endothelial cells
Abdelmejid KANDOUSSI, François MARTIN, Marc HAZZAN, Christian NOËL, Jean-Charles FRUCHART, Bart STAELS, Patrick DURIEZ; HMG-CoA reductase inhibition and PPAR-alpha activation both inhibit cyclosporin A induced endothelin-1 secretion in cultured endothelial cells. Clin Sci (Lond) 1 September 2002; 103 (s2002): 81S–83S. doi: https://doi.org/10.1042/CS103S081S
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