Atorvastatin inhibits angiotensin-converting enzyme induction in differentiating human macrophages

1 Minerva Institute for Medical Research, Helsinki; and 2 Department of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland Submitted 25 August 2006 ; accepted in final form 5 December 2006 Statins are effective drugs in the prevention of cardiovascular disease. Recent studies suggested that statins have additional beneficial effects on the vascular wall independent of their cholesterol-lowering effects. We investigated whether atorvastatin influences angiotensin-converting enzyme (ACE) production in differentiating human macrophages. Human peripheral blood monocytes (PBM) were isolated from fresh buffy coats. The cells were allowed to differentiate for 0–8 days in macrophage serum-free medium with 5 ng/ml granulocyte-macrophage colony-stimulating factor. Atorvastatin (0.005–0.5 µM), mevalonate (200–400 µM), geranylgeranyl pyrophosphate (1.25–2.5 µM), and/or farnesylpyrophosphate (FPP; 1.25–2.5 µM) was added on the second day of differentiation and then every other day. After incubation time, the ACE amount in intact macrophages was measured. ACE amount in PBM was low. A marked time-dependent ACE induction was noticed during differentiation of monocytes to macrophages. Atorvastatin treatment inhibited ACE induction during differentiation. In the presence of mevalonate, atorvastatin failed to downregulate ACE production. Cotreatment of the cells with atorvastatin and FPP reversed the suppressive effect of atorvastatin on ACE. In conclusion, atorvastatin inhibited ACE upregulation, normally occurring in differentiating human macrophages. This effect was mediated via the mevalonate pathway, and inhibition of FPP was probably involved. The finding that atorvastatin inhibited ACE upregulation may represent a novel pleiotropic action and an additional beneficial effect of statins in treatment of cardiovascular disease. cell culture; statin; peripheral blood monocytes; mevalonate Address for reprint requests and other correspondence: O. Saijonmaa, Minerva Institute for Medical Research, Biomedicum Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland (e-mail: outi.saijonmaa{at}helsinki.fi )