Another new target of statins within the BMP pathway is BMPER. enhanced BMPER expression. Increasing concentrations of BMPER exert antiinflammatory features in endothelial cells as reflected by ICAM-1 downregulation. Accordingly, silencing of BMPER enhances ICAM-1 expression. Furthermore mevastatin reduced the expression of proinflammatory BMP4, a well known direct conversation partner of BMPER. Conclusion Mevastatin modulates the BMP pathway by enhancing BMPER via the RhoA/Rock/actin pathway as well as by reducing BMP4 expression. BMP4 down- and BMPER upregulation contribute to the antiinflammatory pleiotropic effects of statins. leads to endothelial dysfunction and arterial hypertension 6, 7. Important insights also came from the discovery of mutations of the BMP receptors in patients with familial pulmonary artery hypertension or teleangiectasia 8. (Rac)-VU 6008667 BMP endothelial cell precursor-derived regulator (BMPER) is a secreted glycoprotein that binds directly to BMPs and modulates their function in a dose dependent fashion. In gain of function assays BMPER behaves as a BMP-antagonist 9, 10, whereas in loss of function models BMPER may also exert pro-BMP functions 11C14. BMPER was originally recognized in a screen for differentially expressed proteins in embryonic endothelial precursor cells 9. In mouse and zebrafish, it is expressed at sites and at the HGFR time of vasculogenesis consistent with a regulatory role for BMPER in vascular events. When BMPER is usually inactivated in zebrafish embryos intersomitic angiogenesis is usually severely perturbed 11. Consistent with this vascular phenotype BMPER may confer proangiogenic activity in endothelial cells in a dose-dependent fashion 15. Taken together, (Rac)-VU 6008667 BMPER functions as a context dependent BMP modulator and is essential for BMP4 function in endothelial cells 15. It has been shown that BMP4 exerts its proinflammatory effects by increased NF-kB activation and induction of ICAM-1 16, 17. ICAM-1 is an adhesion (Rac)-VU 6008667 molecule that is expressed on the endothelium and leukocytes and is upregulated in inflammation by proinflammatory cytokines like TNF-, IL-1, IFN- 18. Increased expression of ICAM-1 was identified in all subtypes of atherosclerotic lesions and is involved in the recruitment of monocytes to the lesion, as suggested by its role in the entry of leukocytes into foci of inflammation. Along the same lines, ICAM-1 enhanced monocyte recruitment is a potential mechanism for the growth of an atherosclerotic plaque 19. Therefore it is important to (Rac)-VU 6008667 understand the regulation of ICAM-1 on the endothelial surface and to identify regulators of ICAM-1 expression because of their potential in the treatment of vascular inflammation. In addition to their ability to lower plasma cholesterol level statins have been shown to decrease ICAM-1 expression in endothelial cells 20, 21. They possess anti-atherogenic properties by improving endothelial function, stabilizing atherosclerotic plaques, reducing oxidative stress as well as endothelial inflammation and thrombogeneity 22. Therefore statins are used in the primary and secondary prevention of cardiovascular disease. By inhibition of the 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase statins block the conversion of HMG-CoA to mevalonate and cause a depletion of isoprenoids such as mevalonate, farnesylpyrophosphate (FPP), and geranylgeranylpyrophosphate (Rac)-VU 6008667 (GGPP). These isoprenoids serve as important lipid anchors for the posttranscriptional modification of small GTPases such as Ras, Rho, Rac and Rap by isoprenylation. Small GTPases are involved in cell signalling and perturbed isoprenylation of small GTPases by statins mediates anti-inflammatory effects partially by downregulation of proinflammatory BMP2 6. In this manuscript we identify the extracellular BMP modulator BMPER as a new mediator of antiinflammatory effects of statins in endothelial cells. Methods Reagents, antibodies, cell culture, immunocytochemistry, transfection of promoter constructs, luciferase assays, RT-PCR, quantitative Real-Time PCR, siRNA transfection, western blotting and animal procedures are described in the online data supplement. Statistical analysis and quantification Statistical analyses were performed using GraphPad Prism 4.0. Data are presented as meanSD, and comparisons were calculated by Students suggesting a class effect of statins on BMPER regulation (Figure 1E). These data were confirmed by treating C57/BL6 mice with subcutaneous.
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