title: The TRIB3 R84 variant is associated with increased carotid intima-media thickness in vivo and with enhanced MAPK signalling in human endothelial cells.
abstract: OBJECTIVE
  TRIB3, a mammalian tribbles homologue, affects insulin signalling and action by inhibiting Akt phosphorylation. A TRIB3 Q84R gain-of-function polymorphism has been associated with insulin resistance both in vitro and in vivo and with several atherosclerotic phenotypes, including increased carotid intima-media thickness (IMT). We wanted to replicate this latter association and, if so, to get deeper insights about the molecular mechanisms underlying the role of the TRIB3 Q84R polymorphism in atherosclerosis.
  
  
  RESULTS
  in 430 Caucasians of European ancestry, carotid IMT was increased in QR (n = 116) and RR (n = 15) when compared with QQ (n = 299) subjects (P= 0.009), thus replicating similar data recently obtained among Asians. In human umbilical vein endothelial cells (HUVECs) naturally carrying the QQ genotype, 24 h insulin stimulation increased monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression, and mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK activation. Conversely, QR- and RR-HUVECs had increased unstimulated monocyte adhesion, VCAM-1 and ICAM-1 expression, and MEK-MAPK activation which did not increase further upon insulin stimulation. In addition, QQ-, QR-, and RR-HUVECs showed similar basal Akt phosphorylation and nitric oxide synthase activity which, however, were significantly increased by insulin only in QQ cells.
  
  
  CONCLUSIONS
  the TRIB3 R4 variant is associated with increased carotid IMT also in Caucasians, thus replicating previous data obtained in Asians. In addition, in HUVECs, this variant is associated with unbalanced insulin signalling. This abnormality may favour vasoreactivity, intima-media thickening, and plaque formation and may, therefore, underlie the deleterious role exerted by the variant on the susceptibility to atherosclerosis.
authors.affiliation: Department of Medicine and Aging Sciences, University 'G. d'Annunzio', Aging Research Center, Ce.S.I., 'G. d'Annunzio' University Foundation, Edificio CeSi, Room 271, University of Chieti, via dei Vestini, 1, 66100 Chieti-Pescara, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Formoso
authors.forename: Pamela
authors.initials: P
authors.lastname: Di Tomo
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.forename: Elena
authors.initials: E
authors.lastname: Succurro
authors.forename: Sara
authors.initials: S
authors.lastname: Di Silvestre
authors.forename: Sabrina
authors.initials: S
authors.lastname: Prudente
authors.forename: Francesco
authors.initials: F
authors.lastname: Perticone
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Trischitta
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
authors.forename: Assunta
authors.initials: A
authors.lastname: Pandolfi
authors.forename: Agostino
authors.initials: A
authors.lastname: Consoli
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017536:Carotid Artery, Common / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology* / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt