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.

Association of the ACE, GSTM1, IL-6, NOS3, and CYP1A1 polymorphisms with susceptibility of mycoplasma pneumoniae pneumonia in Chinese children

“…[25] The variant Asp allele for Glu298Asp polymorphism reduces NOS3 transcriptional activity and NO production in the endothelial cells. [26] …”

Polymorphism of the renin-angiotensin system genes and endothelial NO-synthase gene in obese patients with arterial hypertension

“…The role of gene polymorphism, in particular NOS3 (Glu298Asp), and end-product of glycosylation in the differential response of cells to hyperglycemia has been studied. It is shown that the presence of this genotype contributes to the development of endothelial-dependent vascular complications [42]. Several authors found that the G894T polymorphism of the NOS3 gene is a risk factor for coronary atherosclerosis and HD.…”

Functional relevance of genetic variations of endothelial nitric oxide synthase and vascular endothelial growth factor in diabetic coronary microvessel dysfunction

“…Each of these proteins is intimately related to normal physiological and biochemical function of EC in vivo . Genetic variations in these proteins affect their functional responses and may increase the susceptibility of individuals with these polymorphisms to develop microvascular complications …”

“…Although several genetic variations have been linked to cardiovascular disease, in many cases the mechanisms of each gene variation in disease progression have not been resolved. We have demonstrated that genetic polymorphisms at the level of NOS3 appear to significantly affect EC survival and responses to stress, suggesting that more detailed study of these and other relevant genes and focused mechanistic investigations are warranted to improve our understanding of the prevalence and progression of microvascular complications in diabetic heart disease. Furthermore, understanding the role of specific genetic polymorphisms in disease progression will enable us to develop tailored strategies for individualized treatment in the future.…”

“…This impairment contributes to decreased coronary vascular dilatation in diabetes and may be an important mediator of diabetic cardiovascular complications. Although diminished NOS3 responses are known to occur during diabetes, whether this phenomenon plays a role in microvessel rarefaction has not been resolved.…”