eNOS gene T-786C polymorphism modulates atorvastatin-induced increase in blood nitrite.
Statins inhibit cholesterol synthesis and produce pleiotropic, cholesterol-independent effects including endothelial NO synthase (eNOS) stimulation and increased expression. However, a functional polymorphism in the promoter of the eNOS gene (T-786C) reduces its activity and could modulate the response to statins. Here, we examined whether this polymorphism modulates the effects of atorvastatin on the plasma levels of markers of NO formation and oxidative stress. We genotyped 200 healthy subjects for this polymorphism, and 15 subjects with the TT genotype and 15 with the CC genotype were selected to receive placebo or atorvastatin 10 mg/day po for 14 days. To assess NO bioavailability, the plasma concentrations of nitrate, nitrite, and cGMP and the whole blood nitrite concentrations were determined after placebo or atorvastatin using an ozone-based chemiluminescence assay and an enzyme immunoassay. Thiobarbituric acid-reactive species (TBA-RS) were measured in the plasma to assess oxidative stress. Atorvastatin decreased cholesterol concentrations independent of genotype. Whereas atorvastatin produced no significant changes in plasma nitrite, nitrate, or cGMP concentrations in both genotype groups, atorvastatin increased whole blood nitrite concentrations and decreased plasma TBA-RS concentrations in the CC (but not in the TT) genotype group. These findings suggest that the T-786C polymorphism modulates the effects of atorvastatin on NO bioavailability and oxidative stress.
Nagassaki
Sabrina
S
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
Sertório
Jonas T C
JT
Metzger
Ingrid F
IF
Bem
Andreza F
AF
Rocha
João B T
JB
Tanus-Santos
Jose E
JE
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D000069059:Atorvastatin; D006152:Cyclic GMP / Q000097:blood; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism*; D009573:Nitrites / Q000097:blood*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011758:Pyrroles / Q000494:pharmacology*; D013858:Thiobarbiturates
D006538:Heptanoic Acids; D009573:Nitrites; D011758:Pyrroles; D013858:Thiobarbiturates; D008315:Malondialdehyde; D000069059:Atorvastatin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP; C029684:thiobarbituric acid