title: Atorvastatin completely inhibits VEGF-induced ACE upregulation in human endothelial cells.
abstract: Angiotensin-converting enzyme (ACE) plays an important role in the pathophysiology of cardiovascular disease. We investigated whether atorvastatin, a powerful agent for the prevention and treatment of cardiovascular disease, influences ACE production in endothelial cells. Human umbilical cord vein endothelial cells were treated with VEGF (476 pM), which induced ACE upregulation. Cotreatment with atorvastatin (0.1-10 microM) dose dependently inhibited VEGF-induced ACE upregulation. In the presence of mevalonate (100 microM), atorvastatin failed to downregulate VEGF-induced ACE production. Cotreatment of the cells with either farnesylpyrophosphate (FPP; 5 microM) or geranylgeranylpyrophosphate (GGPP; 5 microM) partially inhibited the suppressive effect of atorvastatin. Pretreatment of the cells with Rho-associated protein kinase inhibitor, Y-27632 (10 microM), partially inhibited VEGF-induced ACE upregulation. VEGF (476 pM) caused PKC phosphorylation, which was inhibited by cotreatment of the cells with atorvastatin. Atorvastatin inhibited VEGF-induced ACE upregulation probably by inhibiting PKC phosphorylation. This effect was mediated via inhibition of the mevalonate pathway. ACE downregulation may be an additional beneficial effect of statins in the treatment of cardiovascular disease.
authors.affiliation: Minerva Institute for Medical Research, Biomedicum Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland. outi.saijonmaa@helsinki.fi
authors.forename: Outi
authors.initials: O
authors.lastname: Saijonmaa
authors.forename: Tuulikki
authors.initials: T
authors.lastname: Nyman
authors.forename: Pia
authors.initials: P
authors.lastname: Stewen
authors.forename: Frej
authors.initials: F
authors.lastname: Fyhrquist
mesh_terms: D000577:Amides / Q000494:pharmacology; D000069059:Atorvastatin; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008798:Mevalonic Acid / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D012717:Sesquiterpenes; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D011758:Pyrroles; D012333:RNA, Messenger; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; C108830:Y 27632; C004808:farnesyl pyrophosphate; D000069059:Atorvastatin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D007703:Peptidyl-Dipeptidase A; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid