Atorvastatin inhibits angiotensin-converting enzyme induction in differentiating human macrophages.
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 microM), mevalonate (200-400 microM), geranylgeranyl pyrophosphate (1.25-2.5 microM), and/or farnesylpyrophosphate (FPP; 1.25-2.5 microM) 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.
Saijonmaa
Outi
O
Minerva Institute for Medical Research, Helsinki, Finland. outi.saijonmaa@helsinki.fi
Nyman
Tuulikki
T
Fyhrquist
Frej
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008798:Mevalonic Acid / Q000378:metabolism / Q000494:pharmacology; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism; D013729:Terpenes / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D012333:RNA, Messenger; D012717:Sesquiterpenes; D013729:Terpenes; C004808:farnesyl pyrophosphate; D000069059:Atorvastatin; D011493:Protein Kinase C; D007703:Peptidyl-Dipeptidase A; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid