© 2000 American Heart Association, Inc.
Molecular Medicine |
Involvement of Rho GTPases in the Transcriptional Inhibition of Preproendothelin-1 Gene Expression by Simvastatin in Vascular Endothelial Cells
From the Centro de Investigaciones Biológicas (O.H.-P., D.P.-S., E.S., S.L.) and Instituto "Reina Sofía" de Investigaciones Nefrológicas, Consejo Superior de Investigaciones Científicas, Velázquez, Madrid, Spain; and Unidad de Investigación (O.H.-P.), Hospital de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain.
Correspondence to Dr Santiago Lamas, Centro de Investigaciones Biológicas, Velázquez 144, 28006 Madrid, Spain. E-mail slamas{at}cib.csic.es
Abstract—Endothelial dysfunction is characterized by an impaired vasodilatory response to endothelial agonists as well as by alterations in adhesion and coagulation processes. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) have been shown to be useful in the reversal of endothelial dysfunction, an effect that may be independent of the reduction in cholesterol levels. Both the L-arginine–nitric oxide–cGMP and endothelin pathways are involved in the regulation of vascular tone. Here, we show that the basal transcription rate of the preproendothelin-1 gene was decreased by simvastatin (10 µmol/L) in bovine aortic endothelial cells. Transfection studies with the preproendothelin-1 gene promoter showed that mevalonate (100 µmol/L) was able to prevent the inhibitory effect mediated by simvastatin. Protein geranylgeranylation, but not farnesylation, proved to be crucial for a correct expression of the preproendothelin-1 gene. The C3 exotoxin from Clostridium botulinum that selectively inactivates Rho GTPases, the processing of which involves geranylgeranylation, reproduced the inhibitory effect of simvastatin on the expression of preproendothelin-1. Overexpression of dominant-negative mutants of RhoA and RhoB led to a significant reduction in the preproendothelin-1 promoter activity, whereas the expression of wild-type and constitutively active forms of these proteins resulted in an increase, in support that Rho proteins are required for the basal expression of the preproendothelin-1 gene. Finally, we show that the Rho-dependent activation of the preproendothelin-1 gene transcription was inhibited by simvastatin. Thus, the control of vascular tone and proliferative response mediated by endothelin-1 is regulated at multiple levels, among which the Rho proteins play an essential role.
Key Words: cholesterol • endothelium • endothelin • GTP-binding proteins • statins
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