title: Prelamin A accumulation in endothelial cells induces premature senescence and functional impairment.
abstract: BACKGROUND
  Defects in lamin A maturation result in premature aging syndromes and severe atherosclerosis as observed in the Hutchinson-Gilford Progeria Syndrome. In age-related atherosclerosis, several features of cellular senescence have been characterized in endothelial cells including telomere shortening and increased oxidative stress. However, to date, very little is known about lamin A alterations in these cells.
  
  
  OBJECTIVE
  To study lamin A-related senescence and its consequences in the activation status of primary endothelial cells.
  
  
  METHODS
  Healthy primary endothelial cells and progenitors issued from human umbilical vein or cord blood were used. Lamin A defects were induced by protease inhibitor (Atazanavir) treatment for 48 h.
  
  
  RESULTS
  We show that protease inhibitor treatment leads to the accumulation of farnesylated prelamin A, inducing nuclear shape abnormalities and premature senescence in both differentiated and progenitor endothelial cells. ICAM-1-dependent activation and monocytes adhesion was increased in mature endothelial cells. In parallel, the ability to generate microvascular networks in matrigel was decreased for endothelial progenitors. The effects of protease inhibitor treatment on nuclear shapes were reversed when cells were treated in combination with Pravastatin and Zoledronate in both mature and progenitor endothelial cells. Reversion was also demonstrated with a morpholino antisense-oligonucleotide targeting lamin A-specific splice site.
  
  
  CONCLUSIONS
  This study shows that protease inhibitor treatment reproduces premature senescence due to lamin A defects in primary endothelial cells and progenitors after 48 h exposure. The cells used were non-aged as extracted from cord blood or umbilical vein, allowing one to consider that other senescence pathways were not activated and that the observed alterations were specific of prelamin A accumulation. Both mature endothelial cells and precursors were sensitive to prelamin accumulation and thus, could be used in the future as a valuable model to test different approaches aimed at specifically reversing lamin A-related cells senescence.
authors.affiliation: APHM, CHU de la Timone, Laboratoire de Génétique Moléculaire, Marseille, France; Aix-Marseille Université, Inserm UMR_S U910, Faculté de Médecine, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonello-Palot
authors.affiliation: Aix-Marseille Université, Inserm, VRCM, UMR_S 1076,13005, Marseille, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Simoncini
authors.affiliation: Aix-Marseille Université, Inserm, VRCM, UMR_S 1076,13005, Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Robert
authors.affiliation: APHM, CHU de la Timone, Laboratoire de Génétique Moléculaire, Marseille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Bourgeois
authors.affiliation: Aix-Marseille Université, Inserm, VRCM, UMR_S 1076,13005, Marseille, France; APHM, CHU de la Conception, Laboratoire de thérapie cellulaire, Marseille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Sabatier
authors.affiliation: APHM, CHU de la Timone, Laboratoire de Génétique Moléculaire, Marseille, France; Aix-Marseille Université, Inserm UMR_S U910, Faculté de Médecine, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levy
authors.affiliation: Aix-Marseille Université, Inserm, VRCM, UMR_S 1076,13005, Marseille, France; AP-HM, CHU de la Conception, Laboratoire d'Hématologie-Immunologie, Marseille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Dignat-George
authors.affiliation: APHM, CHU de la Timone, Laboratoire de Génétique Moléculaire, Marseille, France; Aix-Marseille Université, Inserm UMR_S U910, Faculté de Médecine, Marseille, France. Electronic address: catherine.badens@univ-amu.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Badens
mesh_terms: D000069446:Atazanavir Sulfate; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004164:Diphosphonates / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D034904:Lamin Type A; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000166:cytology; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry; D017035:Pravastatin / Q000737:chemistry; D011371:Progeria / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry; D014470:Umbilical Cord / Q000166:cytology; D014471:Umbilical Veins / Q000166:cytology; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; C573420:ICAM1 protein, human; D007093:Imidazoles; D034904:Lamin Type A; D009687:Nuclear Proteins; D009842:Oligopeptides; D011498:Protein Precursors; D011725:Pyridines; C090764:prelamin A; D018799:Intercellular Adhesion Molecule-1; D000069446:Atazanavir Sulfate; D000077211:Zoledronic Acid; D017035:Pravastatin
keywords: Aging; Atherosclerosis; Lamin A; Senescence; Vascular endothelium