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Am J Physiol Heart Circ Physiol (January 2, 2004). doi:10.1152/ajpheart.00894.2003
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Submitted on September 16, 2003
Accepted on December 30, 2003

Atorvastatin completely inhibits VEGF induced ACE upregulation in human endothelial cells

Outi Saijonmaa1*, Tuulikki Nyman2, Pia Stewen1, and Frej Fyhrquist1

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

* To whom correspondence should be addressed. E-mail: outi.saijonmaa{at}helsinki.fi.

Objective: 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. Methods and Results: Human umbilical cord vein endothelial cells were treated with VEGF (476pM) which induced ACE upregulation. Co-treatment with atorvastatin (0,1-10µM) dose dependently inhibited VEGF induced ACE upregulation. In the presence of mevalonate (100µM), atorvastatin failed to downregulate VEGF induced ACE production. Co-treatment of the cells with either farnesylpyrophosphate (FPP, 5µM) or geranylgeranylpyrophosphate (GGPP, 5µM) partially inhibited the suppressive effect of atorvastatin. Pretreatment of the cells with Rho associated protein kinase inhibitor, Y27632 (10µM), partially inhibited VEGF induced ACE upregulation. VEGF (476pM) caused PKC phosphorylation which was inhibited by co-treatment of the cells with atorvastatin. Conclusions: 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.




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