Cytochrome P450 (CYP) 1B1-Estradiol Metabolite 2-Methoxyestradiol Protects Against Angiotensin II-induced Hypertension By Inhibiting CYP4A1 Expression < And > 20-Hydroxyeicosatetraenoic Acid (20-HETE) Production In The Female Mice

Previously we reported that angiotensin (Ang) II-induced hypertension is mediated by group IV cytosolic phospholipase A 2 α (cPLA 2 α) activation resulting in arachidonic acid (AA) release, and generation predominantly of eicosanoids with prohypertensive effects. Androgen dihydrotestosterone increases the expression of AA metabolizing enzyme cytochrome P450 (CYP) 4A1 and production of 20-HETE in the male rats and mice and an increase in blood pressure (BP). However, female mice that are resistant to Ang II-induced hypertension produce lower renal levels of 20-HETE, compared with males. Cyp4a12a, which has been identified as the predominant 20-HETE producing synthase in the mouse kidney, is expressed in very low levels in the female compared to male mice. Previously, we showed that the protection against Ang II-induced hypertension and associated pathogenesis in the female mice are mediated by CYP1B1-estradiol (E2) generated metabolite 2-methoxyestradiol (2-ME). These observations raised the possibility that CYP1B1-E2 metabolite 2-ME might protect against Ang II-induced hypertension by inhibiting expression of CYP4A1 and 20-HETE production. To test this hypothesis, we examined the effect of 20-HETE receptor antagonist 20-SOLA on Ang II (700 ng/kg/min, s.c. for two weeks)-induced hypertension in 8 weeks old wild type intact, ovariectomized (OVX), and intact Cyp1b1 -/- female mice. The systolic blood pressure (SBP, mmHg) was measured by tail-cuff. At the end of 2 weeks, Ang II caused greater increase in SBP in OVX- Cyp1b1 +/+ (161±6) and Cyp1b1 -/- intact female mice (165±2) compared to the intact Cyp1b1 +/+ mice (128±7) (p<0.05, n=4-5). 20-SOLA (10 mg/kg/day, s.c.), the 20-HETE receptor antagonist minimized Ang II-induced increase in SBP in OVX- Cyp1b1 +/+ (116±4, Δ45) and Cyp1b1 -/- female mice (135±9, Δ30) (P<0.05, n= 4-5). The expression of CYP4A1 was increased in the kidney of OVX- Cyp1b1 +/+ and intact Cyp1b1 -/- compared to intact Cyp1b1 +/+ mice, which was inhibited by E2 in the former but not the later mice; however, 2-ME inhibited CYP4A1 expression in the intact Cyp1b1 -/- mice. These data suggest that CYP1B1-E generated metabolite 2-ME protects against Ang II-induced hypertension by inhibiting the expression of CYP4A1 and production of 20-HETE.