Effects of human endothelial gene polymorphisms on cellular responses to hyperglycaemia: Role of NOS3 (Glu298Asp) and ACE (I/D) polymorphisms

• Published in: Diabetes & vascular disease research 2011-10, Vol.8 (4), p.276-283
• Main Authors: Joshi, Mandar S, Wattanapitayakul, Suvara, Schanbacher, Brandon L, Bauer, John A
• Format: Article
• Language: English
• Subjects: Caveolin 1 - metabolism; Cell Death; Cells, Cultured; Data processing; Diabetes mellitus; Diabetic Angiopathies - enzymology; Diabetic Angiopathies - genetics; Diabetic Angiopathies - pathology; Endothelial cells; Gene polymorphism; Genetic diversity; Genotype; Glucose; Glucose - metabolism; Human Umbilical Vein Endothelial Cells - enzymology; Human Umbilical Vein Endothelial Cells - pathology; Humans; Hyperglycemia - enzymology; Hyperglycemia - genetics; Hyperglycemia - pathology; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Nitrites - metabolism; nitrotyrosine; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Phenotype; Phosphorylation; Polymorphism, Genetic; Proto-Oncogene Proteins c-akt - metabolism; Toxicants; Toxicity; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Vascular diseases
• ISSN: 1479-1641; 1752-8984
• DOI: 10.1177/1479164111416679

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.