title: Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction.
abstract: OBJECTIVE
  Some mutations in LMNA, encoding A-type lamins, are responsible for Dunnigan-type-familial partial lipodystrophy (FPLD2), with altered fat distribution and metabolism. The high prevalence of early and severe cardiovascular outcomes in these patients suggests that, in addition to metabolic risk factors, FPLD2-associated LMNA mutations could have a direct role on the vascular wall cells.
  
  
  RESULTS
  We analyzed the cardiovascular phenotype of 19 FPLD2 patients aged >30 years with LMNA p.R482 heterozygous substitutions, and the effects of p.R482W-prelamin-A overexpression in human coronary artery endothelial cells. In 68% of FPLD2 patients, early atherosclerosis was attested by clinical cardiovascular events, occurring before the age of 45 in most cases. In transduced endothelial cells, exogenous wild-type-prelamin-A was correctly processed and localized, whereas p.R482W-prelamin-A accumulated abnormally at the nuclear envelope. Patients' fibroblasts also showed a predominant nuclear envelope distribution with a decreased rate of prelamin-A maturation. Only p.R482W-prelamin-A induced endothelial dysfunction, with decreased production of NO, increased endothelial adhesion of peripheral blood mononuclear cells, and cellular senescence. p.R482W-prelamin-A also induced oxidative stress, DNA damages, and inflammation. These alterations were prevented by treatment of endothelial cells with pravastatin, which inhibits prelamin-A farnesylation, or with antioxidants. In addition, pravastatin allowed the correct relocalization of p.R482W-prelamin-A within the endothelial cell nucleus. These data suggest that farnesylated p.R482W-prelamin-A accumulation at the nuclear envelope is a toxic event, leading to cellular oxidative stress and endothelial dysfunction.
  
  
  CONCLUSIONS
  LMNA p.R482 mutations, responsible for FPLD2, exert a direct proatherogenic effect in endothelial cells, which could contribute to patients' early atherosclerosis.
authors.affiliation: UPMC Univ Paris 06, UMR_S938, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bidault
authors.forename: Marie
authors.initials: M
authors.lastname: Garcia
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Ducluzeau
authors.forename: Romain
authors.initials: R
authors.lastname: Morichon
authors.forename: Kayathri
authors.initials: K
authors.lastname: Thiyagarajah
authors.forename: Sylviane
authors.initials: S
authors.lastname: Moritz
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.forename: Corinne
authors.initials: C
authors.lastname: Vigouroux
authors.forename: Véronique
authors.initials: V
authors.lastname: Béréziat
mesh_terms: D000328:Adult; D017668:Age of Onset; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D016922:Cellular Senescence; D018920:Coculture Techniques; D004249:DNA Damage; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism*; D052496:Lipodystrophy, Familial Partial / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D054876:Prenylation; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D009569:Nitric Oxide
keywords: arteriosclerosis; endothelial cells; laminin A/C; oxidative stress; prelamin A; statins, HMG-CoA