Abstract 4918: Cytochrome P450 4F2 Transgenic Mice Increase 20-hete and Blood Pressure by Oxidative Stress
Cytochrome P450 4F2 (CYP4F2) is a primary enzyme that converts arachidonic acid (AA) to 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoconstrictive and natriuretic metabolite that regulates human blood pressure. We recently established a CYP4F2 transgenic mouse model using mouse kidney androgen-regulated protein (KAP) promoter, which demonstrated increased 20-HETE production and elevated blood pressure. The present study aims to elucidate the relationship between oxidative stress and 20-HETE in the development of hypertension. The level of oxidative stress was evaluated by measuring malondialdehyde (MDA), a marker of lipid peroxidation, and superoxide dismutase (SOD), a major antioxidative parameter. Plasma MDA was significantly higher in transgenic mice than in wild-type controls (P<0.05), which was consistent with the level of 20-HETE. Plasma SOD activity was decreased in transgenic mice compared with wild-type controls (P<0.05). Kidney homogenate also showed increased MDA and decreased SOD activity. In addition, treatment of 5α-dihydrotestosterone (DHT) strongly induced the synthesis of 20-HETE, and hence enhanced the MDA production and impaired the SOD activity. These results indicate that 20-HETE overproduction in CYP4F2 transgenic mice suffered higher level of oxidative stress. Oxidative stress may possibly be involved in the pathogenesis of 20-HETE-mediated hypertension.