title: LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: Role of ZMPSTE24 downregulation.
abstract: BACKGROUND
  Some LMNA mutations responsible for lipodystrophies, and some HIV-protease inhibitors (PIs) induce accumulation of farnesylated prelamin A and premature senescence in some cell types. Patients with LMNA mutations or under PI-based therapy suffer from early atherosclerosis. The metalloprotease ZMPSTE24 is the key enzyme in prelamin A maturation.
  
  
  OBJECTIVE
  We studied whether altered expression of ZMPSTE24 could contribute to vascular cell dysfunction in response to LMNA mutations or PI treatments.
  
  
  METHODS
  Protein expression of prelamin A and ZMPSTE24 were evaluated in patients' cells and in human cultured VSMCs. Oxidative stress, inflammation, senescence and transdifferentiation/calcification were evaluated in VSMCs.
  
  
  RESULTS
  Fibroblasts from LMNA-mutated lipodystrophic patients (mutations R482W, D47Y or R133L) and peripheral blood mononuclear cells from PI-treated-HIV-infected patients expressed increased prelamin A and decreased ZMPSTE24, which was also observed in VSMCs overexpressing mutant LMNA or treated with PIs. These alterations correlated with oxidative stress, inflammation, senescence and calcification (all p < 0.05). ZMPSTE24 silencing in native VSMCs recapitulated the mutant LMNA- and PI-induced accumulation of farnesylated prelamin A, oxidative stress, inflammation, senescence and calcification. A negative regulator of ZMPSTE24, miRNA-141-3p, was enhanced in LMNA-mutated or PI-treated VSMCs. The farnesylation inhibitors pravastatin and FTI-277, or the antioxidant N-acetyl cysteine, partly restored ZMPSTE24 expression, and concomitantly decreased oxidative stress, inflammation, senescence, and calcification of PI-treated VSCMs.
  
  
  CONCLUSIONS
  ZMPSTE24 downregulation is a major contributor in VSMC dysfunctions resulting from LMNA mutations or PI treatments that could translate in early atherosclerosis at the clinical level. These novel pathophysiological mechanisms could open new therapeutic perspectives for cardiovascular aging.
authors.affiliation: Inserm, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France; ICAN, Institute of Cardiometabolism and Nutrition, F-75013 Paris, France. Electronic address: pauline.afonso@gmail.com.
authors.forename: Pauline
authors.initials: P
authors.lastname: Afonso
authors.affiliation: Inserm, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France; ICAN, Institute of Cardiometabolism and Nutrition, F-75013 Paris, France. Electronic address: martine.auclair@inserm.fr.
authors.forename: Martine
authors.initials: M
authors.lastname: Auclair
authors.affiliation: Inserm, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France; AP-HP, Hôpital Saint-Antoine, Service de Cardiologie, F-75012 Paris, France. Electronic address: franck.boccara@aphp.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Boccara
authors.affiliation: Centre Hospitalier Régional Universitaire de Lille, Service d'Endocrinologie et Métabolisme, F-59037 Lille, France. Electronic address: marie-christine.vantyghem@chru-lille.fr.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.affiliation: Inserm, UMR_S 1136, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France; AP-HP, Hôpital de la Pitié-Salpêtrière, Service des Maladies Infectieuses et Tropicales, F-75013 Paris, France. Electronic address: christine.katlama@aphp.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.affiliation: Inserm, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France; AP-HP, Hôpital Tenon, Service de Biochimie et Hormonologie, F-75020 Paris, France; ICAN, Institute of Cardiometabolism and Nutrition, F-75013 Paris, France. Electronic address: jacqueline.capeau@inserm.fr.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.affiliation: Inserm, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France; AP-HP, Hôpital Saint-Antoine, Laboratoire Commun de Biologie et Génétique Moléculaires, F-75012 Paris, France; ICAN, Institute of Cardiometabolism and Nutrition, F-75013 Paris, France. Electronic address: corinne.vigouroux@inserm.fr.
authors.forename: Corinne
authors.initials: C
authors.lastname: Vigouroux
authors.affiliation: Inserm, UMR_S 938, Centre de Recherche Saint-Antoine, F-75012, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, F-75005 Paris, France; ICAN, Institute of Cardiometabolism and Nutrition, F-75013 Paris, France. Electronic address: martine.debarle@inserm.fr.
authors.forename: Martine
authors.initials: M
authors.lastname: Caron-Debarle
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008060:Lipodystrophy / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D061205:Vascular Calcification / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: D017320:HIV Protease Inhibitors; C494847:LMNA protein, human; D034904:Lamin Type A; D008565:Membrane Proteins; D004247:DNA; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human
keywords: Atherosclerosis; Osteogenic transdifferentiation; Prelamin A; Senescence; Vascular smooth muscle cells; ZMPSTE24