Abstract 5430: Statins Exert Pleiotropic Effects by Enhancement of BMPER Expression via the Rho/Rock Pathway in Endothelial Cells

Abstract

Background Statins exert pleiotropic effects on endothelial cells besides cholesterol lowering. Bone morphogenetic proteins (BMPs) have recently been implicated in vascular inflammation and disease. We set out to investigate the effect of statins on BMPER, a novel member of the BMP pathway.

Methods and Results Mevastatin or simvastatin enhanced BMPER expression in endothelial cells in a time and concentration dependent manner as determined by immunocytochemistry, RT-PCR, and western blotting. Actinomycin D chase analysis and BMPER promoter studies with reporter assays revealed that this is predominantly a post-transcriptional effect resulting in a prolonged BMPER RNA half-life. Rescue experiments using downstream metabolites of the HMG-CoA pathway (mevalonate, GPP, GGPP) suggested that the RhoA/Rock/actin pathway would be involved in BMPER regulation. Indeed we confirmed that the RhoA/Rock/actin pathway is essential for BMPER regulation using the specific pathway activator CNFY. CNFY prevented the upregulation of BMPER by mevastatin whereas pathway inhibitors (C3-toxin, RhoAN19 mutant, fasudil, cytochalasin D) enhanced BMPER expression. As reflected by ICAM-1 regulation BMPER has anti-inflammatory features. Increasing concentrations of BMPER reduced ICAM-1 expression while silencing of BMPER increased ICAM-1 in endothelial cells. Remarkably, mevastatin reduced the expression of proinflammatory BMP4, a direct interaction partner of BMPER.

Conclusion Mevastatin modulates the BMP pathway by enhancing BMPER expression via the RhoA/Rock/actin pathway as well as by inhibiting BMP4 expression. BMP4 down- and BMPER upregulation contribute to the anti-inflammatory pleiotropic effects of statins and represent a novel pleiotropic mechanism.