BMPER is upregulated by statins and modulates endothelial inflammation by intercellular adhesion molecule-1.
OBJECTIVE
In addition to lowering cholesterol, statins exert pleiotropic effects on endothelial cells. Bone morphogenetic proteins (BMPs) have recently been implicated in vascular inflammation and disease. We set out to investigate the effect of statins on BMP endothelial cell precursor-derived regulator (BMPER), a novel member of the BMP pathway.


RESULTS
Mevastatin enhanced BMPER expression in cultured endothelial cells in a time- and concentration-dependent manner as determined by immunocytochemistry, RT-PCR, and Western blotting. Similar effects were observed in vitro and in vivo using simvastatin. Actinomycin D chase analysis and BMPER promoter reporter assays revealed that this is mostly a posttranscriptional event resulting in prolonged BMPER RNA half-life. We confirmed that the RhoA/Rho-associated coiled-coil containing protein kinase Rho kinase (Rock)/actin pathway is involved using the specific pathway activator cytotoxic necrotizing factor of Yersinia pseudotuberculosis, which prevented upregulation of BMPER expression by mevastatin and pathway inhibitors (C3-toxin, RhoAN19 mutant, fasudil, and cytochalasin D) that enhanced BMPER expression. Increasing concentrations of BMPER exert antiinflammatory features in endothelial cells as reflected by intercellular adhesion molecule-1 downregulation. Accordingly, silencing of BMPER enhances intercellular adhesion molecule-1 expression. Furthermore, mevastatin reduced the expression of proinflammatory BMP4, a well-known direct interaction partner of BMPER.


CONCLUSIONS
Mevastatin modulates the BMP pathway by enhancing BMPER via the RhoA/Rock/actin pathway, as well as by reducing BMP4 expression. BMP4 downregulation and BMPER upregulation contribute to the antiinflammatory pleiotropic effects of statins.
Helbing
Thomas
T
Department for Cardiology, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
Rothweiler
René
R
Heinke
Jennifer
J
Goetz
Lena
L
Diehl
Philipp
P
Zirlik
Andreas
A
Patterson
Cam
C
Bode
Christoph
C
Moser
Martin
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; C476724:BMPER protein, human; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C517553:crossveinless 2 protein, mouse; D018799:Intercellular Adhesion Molecule-1; C012258:mevastatin; D008148:Lovastatin; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein