title: C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling.
abstract: Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease.
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oller
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain Unidad de Biotecnología Celular, Instituto de Investigación en Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Arántzazu
authors.initials: A
authors.lastname: Alfranca
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Méndez-Barbero
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Villahoz
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Lozano-Vidal
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Mara
authors.initials: M
authors.lastname: Martín-Alonso
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Alicia G
authors.initials: AG
authors.lastname: Arroyo
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Amelia
authors.initials: A
authors.lastname: Escolano
authors.affiliation: Research Institute in Healthcare Science, School of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, United Kingdom.
authors.forename: Angel Luis
authors.initials: AL
authors.lastname: Armesilla
authors.affiliation: Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain mcampanero@iib.uam.es jmredondo@cnic.es.
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Campanero
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain mcampanero@iib.uam.es jmredondo@cnic.es.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D000818:Animals; D001011:Aorta / Q000201:enzymology; D001483:Base Sequence; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D019703:Calcineurin / Q000378:metabolism; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D066253:Vascular Remodeling
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D050778:NFATC Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019703:Calcineurin; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C486323:Adamts1 protein, mouse