Abstract 17228: BMPER is a Modulator of Vascular Inflammation and Endothelial Cell Dysfunction
Introduction: Bone Morphogenetic Proteins (BMPs) are important regulators of vascular disease and contribute to the progression of atherosclerosis. Bone morphogenetic protein endothelial cell precursor derived regulator (BMPER) is a new member of the BMP family which in earlier studies was found to be up-regulated by statins and confers some of their pleiotropic effects. Here we describe the role of BMPER in vascular inflammation and endothelial cell dysfunction.
Methods and results: Endothelial cells (ECs) were challenged with TNFα or thrombin. Indeed BMPER promoter activity, RNA and protein levels were down-regulated as detected by reporter assays, quantitative PCR and western blotting. In vivo inflammation was induced by i.p. application of lipopolysaccharide in mice and confirmed BMPER down-regulation. Mechanistically we found that BMPER is regulated involving the anti-inflammatory Kruepple-like factor 2 (KLF2) and the Rho/ROCK pathway. Downregulation of KLF2 by siRNA reduced BMPER protein expression whereas overexpression of KLF2 had the opposite effect. Cotreatment of ECs with thrombin and the ROCK inhibitor Y27632 abolished the thrombin induced down-regulation of BMPER. Next we hypothesized that lack of BMPER enhances inflammation. We observed that siRNA induced BMPER knock down up-regulates ICAM-1 and VCAM but down-regulates eNOS. Functionally, BMPER knock down enhanced leukocyte adhesion to endothelial cells in flow chamber experiments. Accordingly, in aseptic peritonitis in mice more monocytes were recruited into the ascites of BMPER +/− mice compared with wild-type. Vice versa, stimulation of EC with BMPER increased eNOS levels in a concentration dependent manner and abolished TNFα-induced ICAM-1 and VCAM expression in EC. In flow chamber experiments BMPER inhibited TNFα induced leukocyte adhesion demonstrating that BMPER has anti-inflammatory properties.
Conclusion We identified BMPER as a new anti-inflammatory regulator of endothelial cell homeostasis. Down-regulation of BMPER expression is observed in inflammation and leads to increased leukocyte adhesion and recruitment. On the other hand BMPER mediates beneficial effects on EC by attenuating endothelial inflammation.
- © 2010 by American Heart Association, Inc.