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Atorvastatin completely inhibits VEGF-induced ACE upregulation in human endothelial cells

¹Minerva Institute for Medical Research, FIN-00290 Helsinki; and ²Department of Internal Medicine, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland

Submitted 16 September 2003 ; accepted in final form 30 December 2003

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 µM) dose dependently inhibited VEGF-induced ACE upregulation. In the presence of mevalonate (100 µM), atorvastatin failed to downregulate VEGF-induced ACE production. Cotreatment of the cells with either farnesylpyrophosphate (FPP; 5 µM) or geranylgeranylpyrophosphate (GGPP; 5 µM) partially inhibited the suppressive effect of atorvastatin. Pretreatment of the cells with Rho-associated protein kinase inhibitor, Y-27632 (10 µM), 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.

mevalonate pathway; PKC; statins; renin-angiotensin system

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