Abstract 627: Regulation of Nuclear Factor of Activated T Cells by BMP-Binding Endothelial Regulator Signaling
Dysfunction of the vascular endothelium results in various cardiovascular, circulatory and blood diseases and exemplifies the importance of endothelial integrity. BMP-binding endothelial regulator (BMPER), a well recognized extracellular modulator of Bone morphogenetic protein (BMP) signaling, has been identified as a vital component in the vascular response to stress. Microarray analysis revealed nuclear factor of activated T cells (NFAT) as one of the genes found to be most highly upregulated by BMPER treatment in mouse endothelial cells (MECs), as well as many genes with NFAT consensus binding sites. Therefore we hypothesize that BMPER is an important regulator of NFAT transcriptional activity. Initially we have investigated the effect of BMPER on NFATc1 activation with MECs and human primary endothelial cells. Our data show that the translocation of NFATc1 from the cytoplasm to the nucleus following BMPER treatment, determined by immunofluorescent analysis. By using the nuclear fractionation assays, we observed the similar result that the translocation of NFATc1 to the nucleus of HUVECs took place after 30 minutes of BMPER treatment. Next, we wanted to determine whether the increased NFATc1 protein level in nucleus results in the enhanced transcriptional activity. Indeed, when HUVECs are treated with BMPER and then analyzed with luciferase reporter assay, a 1.5-fold significant increase in NFAT activity over baseline was observed. Our previous data demonstrate that LDL receptor related protein (LRP1) interacts with BMPER and regulates BMPER’s activity through endocytosis in endothelial cells. Interesting, we observe that LRP1 also interacts with NF45, the 45-kDa subunit of NFAT protein. It strongly suggests that BMPER positively regulates NFAT activity through LRP1. This novel signaling pathway indicates that BMPER may acts as a new ligand and exhibits BMP-independent activity in endothelial cells and therefore contribute to the regulation of vascular homeostasis.
Author Disclosures: P.P. Lockyer: None. H. Mao: None. X. Li: None. X. Pi: None.
- © 2015 by American Heart Association, Inc.