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Core 7: Vascular Disease: Biology and Clinical Science (Non-interventional)

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

Thomas Helbing, Rene Rothweiler, Jennifer Heinke, Lena Goetz, Philipp Diehl, Cam Patterson, Christoph Bode, Martin Moser
Circulation. 2009;120:S1091
Thomas Helbing
Univ of Freiburg, Freiburg, Germany
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Rene Rothweiler
Univ of Freiburg, Freiburg, Germany
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Jennifer Heinke
Univ of Freiburg, Freiburg, Germany
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Lena Goetz
Univ of Freiburg, Freiburg, Germany
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Philipp Diehl
Univ of Freiburg, Freiburg, Germany
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Cam Patterson
Univ of North Carolina, Chapel Hill, NC
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Christoph Bode
Univ of Freiburg, Freiburg, Germany
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Martin Moser
Univ of Freiburg, Freiburg, Germany
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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.

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Circulation
November 3, 2009, Volume 120, Issue Suppl 18
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    Abstract 5430: Statins Exert Pleiotropic Effects by Enhancement of BMPER Expression via the Rho/Rock Pathway in Endothelial Cells
    Thomas Helbing, Rene Rothweiler, Jennifer Heinke, Lena Goetz, Philipp Diehl, Cam Patterson, Christoph Bode and Martin Moser
    Circulation. 2009;120:S1091, originally published January 5, 2016

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    Abstract 5430: Statins Exert Pleiotropic Effects by Enhancement of BMPER Expression via the Rho/Rock Pathway in Endothelial Cells
    Thomas Helbing, Rene Rothweiler, Jennifer Heinke, Lena Goetz, Philipp Diehl, Cam Patterson, Christoph Bode and Martin Moser
    Circulation. 2009;120:S1091, originally published January 5, 2016
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