title: Transcription factor KLF6 upregulates expression of metalloprotease MMP14 and subsequent release of soluble endoglin during vascular injury.
abstract: After endothelial injury, the transcription factor Krüppel-like factor 6 (KLF6) translocates into the cell nucleus to regulate a variety of target genes involved in angiogenesis, vascular repair and remodeling, including components of the membrane transforming growth factor beta (TGF-β) receptor complex such as endoglin and activin receptor-like kinase 1. The membrane metalloproteinase 14 (MMP14 or MT1-MMP) targets endoglin to release soluble endoglin and is involved in vascular inflammation and endothelial tubulogenesis. However, little is known about the regulation of MMP14 expression during vascular wounding. In vitro denudation of monolayers of human endothelial cell monolayers leads to an increase in the KLF6 gene transcriptional rate, followed by an upregulation of MMP14 and release of soluble endoglin. Concomitant with this process, MMP14 co-localizes with endoglin in the sprouting endothelial cells surrounding the wound border. MMP14 expression at mRNA and protein levels is increased by ectopic KLF6 and downregulated by KLF6 suppression in cultured endothelial cells. Moreover, after wire-induced endothelial denudation, Klf6 (+/-) mice show lower levels of MMP14 in their vasculature compared with their wild-type siblings. Ectopic cellular expression of KLF6 results in an increased transcription rate of MMP14, and chromatin immunoprecipitation assays show that KLF6 interacts with MMP14 promoter in ECs, this interaction being enhanced during wound healing. Furthermore, KLF6 markedly increases the transcriptional activity of different reporter constructs of MMP14 gene promoter. These results suggest that KLF6 regulates MMP14 transcription and is a critical player of the gene expression network triggered during endothelial repair.
authors: Centro de Investigaciones Biológicas, CSIC, c/Ramiro de Maeztu 9, Madrid, 28040, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28040, Spain.
authors: Eunate
authors: E
authors: Gallardo-Vara
authors: Centro de Investigaciones Biológicas, CSIC, c/Ramiro de Maeztu 9, Madrid, 28040, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28040, Spain.
authors: Francisco J
authors: FJ
authors: Blanco
authors: Servei de Cardiologia, Hospital Clínic i Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors: Mercè
authors: M
authors: Roqué
authors: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Scott L
authors: SL
authors: Friedman
authors: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.|National Institute for Health Research, Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors: Toru
authors: T
authors: Suzuki
authors: Centro de Investigaciones Biológicas, CSIC, c/Ramiro de Maeztu 9, Madrid, 28040, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28040, Spain.
authors: Luisa M
authors: LM
authors: Botella
authors: Centro de Investigaciones Biológicas, CSIC, c/Ramiro de Maeztu 9, Madrid, 28040, Spain. bernabeu.c@cib.csic.es.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28040, Spain. bernabeu.c@cib.csic.es.
authors: Carmelo
authors: C
authors: Bernabeu
mesh_terms: D000818:Animals; D001483:Base Sequence; D003198:Computer Simulation; D000071063:Endoglin / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D057772:Vascular System Injuries / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D014945:Wound Healing
chemical_list: C064206:ENG protein, human; D000071063:Endoglin; C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D053511:Matrix Metalloproteinase 14
keywords: Endothelial cells; KLF6; MMP14; Soluble endoglin; Transcription; Vascular injury