title: Effects of human endothelial gene polymorphisms on cellular responses to hyperglycaemia: role of NOS3 (Glu298Asp) and ACE (I/D) polymorphisms.
abstract: The functional relevance of NOS3 and ACE genetic variations to endothelial cell function is largely unstudied. Here we tested the functional relevance of the NOS3 (Glu298Asp) polymorphism and ACE (I/D) polymorphism in endothelial cells in vitro. Our hypothesis was that these genetic polymorphisms alter endothelial cell sensitivity to glucose and 3-nitrotyrosine (3NT). Genotyped HUVECs were incubated with glucose, free 3NT or a combination of these two toxicants. Significant differences in glucose-induced cell death and free 3NT-induced cell death were observed among the NOS3 genotypes. Combined glucose/3NT caused increased toxicity among the NOS3 genotypes. No differences were observed among the ACE genotypes in their responses to glucose/3NT. These data demonstrate that the NOS3 genotype may be an important predictor of, or be mechanistically involved in, endothelial vulnerability, whereas the ACE I/D genotype is apparently less important. Thus this NOS3 genetic variation may play a role in vulnerability to endothelium-dependent diabetic vascular complications.
authors.affiliation: The Ritchie Centre, Monash Institute of Medical Research, Clayton VIC, Australia. Mandar.joshi@monash.edu
authors.forename: Mandar S
authors.initials: MS
authors.lastname: Joshi
authors.forename: Suvara
authors.initials: S
authors.lastname: Wattanapitayakul
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Schanbacher
authors.forename: John A
authors.initials: JA
authors.lastname: Bauer
mesh_terms: D051242:Caveolin 1 / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D009573:Nitrites; C002744:3-nitrotyrosine; D014443:Tyrosine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D007703:Peptidyl-Dipeptidase A; D005947:Glucose