title: PAFAH1B1 and the lncRNA NONHSAT073641 maintain an angiogenic phenotype in human endothelial cells.
abstract: Platelet-activating factor acetyl hydrolase 1B1 (PAFAH1B1, also known as Lis1) is a protein essentially involved in neurogenesis and mostly studied in the nervous system. As we observed a significant expression of PAFAH1B1 in the vascular system, we hypothesized that PAFAH1B1 is important during angiogenesis of endothelial cells as well as in human vascular diseases.
  
  
  
  The functional relevance of the protein in endothelial cell angiogenic function, its downstream targets and the influence of NONHSAT073641, a long non-coding RNA (lncRNA) with 92% similarity to PAFAH1B1, were studied by knockdown and overexpression in human umbilical vein endothelial cells (HUVEC).
  
  
  
  Knockdown of PAFAH1B1 led to impaired tube formation of HUVEC and decreased sprouting in the spheroid assay. Accordingly, the overexpression of PAFAH1B1 increased tube number, sprout length and sprout number. LncRNA NONHSAT073641 behaved similarly. Microarray analysis after PAFAH1B1 knockdown and its overexpression indicated that the protein maintains Matrix Gla Protein (MGP) expression. Chromatin immunoprecipitation experiments revealed that PAFAH1B1 is required for active histone marks and proper binding of RNA Polymerase II to the transcriptional start site of MGP. MGP itself was required for endothelial angiogenic capacity and knockdown of both, PAFAH1B1 and MGP, reduced migration. In vascular samples of patients with chronic thromboembolic pulmonary hypertension (CTEPH), PAFAH1B1 and MGP were upregulated. The function of PAFAH1B1 required the presence of the intact protein as overexpression of NONHSAT073641, which was highly upregulated during CTEPH, did not affect PAFAH1B1 target genes.
  
  
  
  PAFAH1B1 and NONHSAT073641 are important for endothelial angiogenic function.
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Josipovic
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Fork
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Preussner
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: K-K
authors.initials: KK
authors.lastname: Prior
authors.affiliation: Department of Lung Development and Remodeling, German Center for Lung Research (DZL), Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Iloska
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: A E
authors.initials: AE
authors.lastname: Vasconez
authors.affiliation: Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Labocha
authors.affiliation: Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Angioni
authors.affiliation: Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Looso
authors.affiliation: Department of Lung Development and Remodeling, German Center for Lung Research (DZL), Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.|Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University, Giessen, Germany.
authors.forename: S S
authors.initials: SS
authors.lastname: Pullamsetti
authors.affiliation: Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Frankfurt, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: R P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
authors.forename: M S
authors.initials: MS
authors.lastname: Leisegang
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D012319:RNA Polymerase II / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000502:physiology; D013923:Thromboembolism / Q000150:complications / Q000378:metabolism; D014945:Wound Healing; D000097568:Matrix Gla Protein
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D006657:Histones; D006893:Hydroxyeicosatetraenoic Acids; D008869:Microtubule-Associated Proteins; D012319:RNA Polymerase II; D062085:RNA, Long Noncoding; D000097568:Matrix Gla Protein; C084102:PAFAH1B1 protein, human
keywords: HETE; Matrix Gla Protein; PAFAH1B1; angiogenesis; lncRNA; pulmonary hypertension