We previously generated cytochrome P450 4F2 (CYP4F2) transgenic mice and showed high 20-hydroxyeicosatetraenoic acid (20-HETE) production, which resulted in an elevation of blood pressure. However, it was unclear whether 20-HETE affected glucose metabolism. We measured fasting plasma glucose, insulin, hepatic CYP4F2 expression, and 20-HETE production by hepatic microsomes, and hepatic 20-HETE levels in transgenic mice. We also assessed glycogen phosphorylase (GP) activity and the cAMP/protein kinase A (PKA)-phosphorylase kinase (PhK)-GP pathway, as well as expressions of insulin receptor substrate 1 and glucose transporters in vivo and in vitro. The transgenic mice had overexpressed hepatic CYP4F2, high hepatic 20-HETE and fasting plasma glucose levels but normal insulin level. The GP activity was increased and the cAMP/PKA-PhK-GP pathway was activated in the transgenic mice compared with wild-type mice. Moreover, these alterations were eliminated with the addition of N-hydroxy-N′-(4-butyl-2 methylphenyl) formamidine, which is a selective 20-HETE inhibitor. The results were further validated in Bel7402 cells. In addition, the transgenic mice had functional insulin signaling, and 20-HETE had no effect on insulin signaling in Bel7402 cells, excluding that the observed hyperglycemia in CYP4F2 transgenic mice resulted from insulin dysfunction, because the target tissues were sensitive to insulin. Our study suggested that 20-HETE can induce hyperglycemia, at least in part, through the cAMP/PKA-PhK-GP pathway but not through the insulin-signaling pathway.

Oxidative stress, characterized by increased reactive oxygen species production and/or decreased antioxidant enzyme activity, plays an important role in the pathogenesis of hypertension. The identification of molecular markers corresponding to the oxidative stress status of hypertension may assist in the antioxidant therapy of hypertension. In the present study, superoxide dismutase (SOD) and endothelial nitric oxide synthase (eNOS) were analyzed as markers of hypertension responding to oxidative stress. The plasma SOD activity and mononitrogen oxides (NOx) concentration were measured, and the SOD3 Ala58Thr and eNOS Glu298Asp polymorphisms were genotyped in hypertensive patients and normotensive controls. Further association experiments were replicated in an extended population, including 343 hypertensive patients and 290 controls. The results demonstrated that no statistically significant differences in the total SOD activity and NOx concentration were identified between the hypertensive patients and controls. However, the plasma SOD activity levels in the SOD3 Ala/Ala homozygote carriers (80.51±27.68 U/ml) were significantly lower compared with the Thr allele carriers (92.18±16.37 U/ml; P=0.031). In addition, the plasma NOx concentration in the eNOS Glu/Glu homozygote carriers (129.66±59.15 µmol/l) was significantly lower compared with the Asp allele carriers (169.84± 55.18 µmol/l; P=0.010). Notably, the altered SOD activity levels and NOx concentration were in concordance in 56.3% of the 80 participants. Therefore, the concordance of decreased SOD activity and NOx concentration, combined with genotypes of SOD3 Ala/Ala and/or eNOS Glu/Glu in hypertensive patients, may be useful in directing the antioxidant therapy of hypertension.