Abstract P303: Inhibition of Group IV Cytosolic Phospholipase A 2 α by Cytochrome P450 1B1-Estradiol Derived Metabolite 2-Methoxyestradiol Protects Against Angiotensin II-Induced Hypertension in Female Mice

Abstract

Previously we showed that the protection against angiotensin (Ang) II-induced hypertension and associated pathophysiological changes in female mice are mediated by cytochrome P450 (CYP) 1B1-estradiol (E2) generated metabolite 2-methoxyestradiol (2-ME). Also, we demonstrated that 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 pro-hypertensive effects in male mice. This study was conducted to determine the contribution of cPLA 2 α/AA system, and its relationship to CYP1B1 in Ang II-induced hypertension in the female mice. Ang II infusion (700 ng/kg/min, s.c. micro-osmotic pump) for 14 days increased the systolic blood pressure (SBP), measured by tail-cuff in wild-type mice (cPLA 2 α +/+ ) but not in cPLA 2 α gene-disrupted mice (cPLA 2 α -/- ) (151±8 vs. 126±9 mmHg, P <0.05, n=4-5). Ang II markedly increased SBP in ovariectomized (OVX) cPLA 2 α +/+ mice but not in OVX cPLA 2 α -/- mice (175±3 vs. 121±2 mmHg, P <0.05, n=4-5). AA metabolism inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA, 50 mg/kg, i.p. every 3 rd day) attenuated ( P <0.05) the Ang II-induced increase in SBP in intact (124±5 mmHg, n=5) and OVX cPLA 2 α +/+ mice (124±5 mmHg, n=4). E2 attenuated Ang II-induced increase in SBP in OVX Cyp1b1 +/+ mice, but not in OVX Cyp1b1 -/- mice (125±5 vs. 158±4 mmHg, P <0.05, n=3-4). Ang II-induced increase in SBP was also attenuated by ETYA in the Cyp1b1 -/- mice (129±7 vs. 185±7 mmHg, P <0.05, n=4). Ang II-induced increase in cPLA 2 α +/+ activity examined in the kidneys was inhibited in Cyp1b1 -/- mice treated with 2-ME. Antagonists of prostaglandin (PG) E2 receptors EP1 (SC19220) and EP3 (L-798106) (28 μg/g, s.c. every 2 nd day) minimized Ang II-induced increase in SBP in OVX cPLA 2 α +/+ mice (126±2 and 127±5 vs. 175±3 mmHg, respectively, n=5). These data suggest that CYP1B1-E2 generated metabolite 2-ME protects against Ang II-induced hypertension by inhibiting cPLA 2 α activity and production of AA-derived PGE2 that exerts pro-hypertensive effects by stimulating EP1 and EP3 receptors. Thus, 2-ME and the drugs that selectively block EP1 and EP3 receptors could be useful for the treatment of hypertension and its pathogenesis in females.