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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 30, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp136
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Statins normalize vascular lysyl oxidase down-regulation induced by proatherogenic risk factors

Cristina Rodríguez*, Javier F. Alcudia, José Martínez-González, Anna Guadall, Berta Raposo, Sonia Sánchez-Gómez and Lina Badimon

Centro de Investigación Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

* Correspondence: Dra. Cristina Rodríguez Centro de Investigación Cardiovascular (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (pabellón Nº 11) Antoni Ma Claret 167 08025 Barcelona, Spain TEL: +34 935565897; FAX: +34 935565559 E-mail: crodriguezs{at}csic-iccc.org

Aims: Statins are lipid-lowering drugs widely used in the management of vascular diseases. Clinical and experimental evidence suggest that statins improve endothelial function by both cholesterol lowering-dependent and -independent mechanisms. We have previously shown that endothelial dysfunction induced by risk factors and proinflammatory cytokines is associated with down-regulation of lysyl oxidase (LOX), a key enzyme modulating extracellular matrix maturation and vascular integrity. Our aim was to analyze whether statins could normalize LOX expression impaired by proatherogenic risk factors.

Methods and Results: We observed that pharmacological concentrations of statins (atorvastatin and simvastatin) modulated LOX transcriptional activity, counteracting the down-regulation of LOX (at the mRNA, protein and activity level) caused by tumour necrosis factor-{alpha} (TNF{alpha}) in porcine, bovine and human aortic endothelial cells. Geranylgeraniol but not farnesol reversed this effect, suggesting the involvement of geranylgeranylated proteins. In accordance, inhibitors of RhoA/Rho kinase also counteracted LOX down-regulation caused by TNF{alpha}, and over-expression of a RhoA dominant-negative mutant mimicked statin effects. Statins were also able to counteract the decrease of LOX expression produced by atherogenic concentrations of LDL by a similar mechanism and to partially prevent the increase in endothelial permeability elicited by these lipoproteins. Finally, in the in vivo porcine model of hypercholesterolemia, we observed that statins abrogated the reduction of vascular LOX expression triggered by high plasma levels of LDL.

Conclusions: These data indicate that statins normalize vascular LOX expression altered by atherogenic risk factors through a RhoA/Rho kinase-dependent mechanism. Thus, modulation of LOX by statins could contribute to vascular protection and to the cardiovascular risk reduction achieved by this therapy.

Time for primary review: 17 Days

The first two authors contribute equally to this work


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