title: A novel truncated form of eNOS associates with altered vascular function.
abstract: OBJECTIVE
  Nitric oxide (NO) plays a key role in vascular homeostasis and is produced by endothelial NO synthase (eNOS), encoded by NOS3 gene. We previously reported the genetic association between NOS3 rs753482-A>C polymorphism on intron 19 and coronary artery disease (CAD). In the attempt of conferring functional implication to the rs753482-A>C polymorphism, we investigated its influence on transcript maturation.
  
  
  RESULTS
  A transcript variant skipping exons 20-21 is prevalent in carriers of the rs753482-C allele and is translated in a novel truncated form of eNOS. The truncated eNOS displays increased basal NO production, is insensitive to calcium stimulation, and, upon heterodimerization with the full-length eNOS protein, exerts a dominant-negative effect on NO production. CAD patients and healthy subjects' carriers of the rs753482-C genotype are characterized by increased NO basal levels in peripheral blood and platelets, and negatively respond to oral glucose load by failing to increase NO synthesis following insulin wave. Furthermore, forearm vasodilation after reactive hyperaemia is dramatically impaired in rs753482-C carriers.
  
  
  CONCLUSIONS
  We demonstrated that subjects carrying the rs753482-C genotype express a novel stable truncated form of eNOS with altered enzymatic activity that influences NO production and endothelial function. These findings open to new intriguing perspectives to several diseases involving vascular response to NO.
authors.affiliation: Cardio-Diabetes and Core Lab, Division of Metabolic and Cardiovascular Science, San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Galluccio
authors.forename: Laura
authors.initials: L
authors.lastname: Cassina
authors.forename: Isabella
authors.initials: I
authors.lastname: Russo
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gelmini
authors.forename: Emanuela
authors.initials: E
authors.lastname: Setola
authors.forename: Luca
authors.initials: L
authors.lastname: Rampoldi
authors.forename: Lorena
authors.initials: L
authors.lastname: Citterio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rossodivita
authors.forename: Mikel
authors.initials: M
authors.lastname: Kamami
authors.forename: Antonio
authors.initials: A
authors.lastname: Colombo
authors.forename: Ottavio
authors.initials: O
authors.lastname: Alfieri
authors.forename: Marina
authors.initials: M
authors.lastname: Carini
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bosi
authors.forename: Mariella
authors.initials: M
authors.lastname: Trovati
authors.forename: Piermarco
authors.initials: P
authors.lastname: Piatti
authors.forename: Lucilla D
authors.initials: LD
authors.lastname: Monti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Casari
mesh_terms: D000328:Adult; D000368:Aged; D003324:Coronary Artery Disease / Q000201:enzymology / Q000235:genetics*; D004730:Endothelium, Vascular / Q000201:enzymology*; D005787:Gene Frequency / Q000235:genetics* / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D014664:Vasodilation / Q000502:physiology
chemical_list: C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: Endothelial function; Nitric oxide; Novel isoform; eNOS