2-Methoxyestradiol Ameliorates Angiotensin II-Induced Hypertension by Inhibiting Cytosolic Phospholipase A

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We tested the hypothesis that CYP1B1 (cytochrome P450 1B1)-17β-estradiol metabolite 2-methoxyestradiol protects against Ang II (angiotensin II)–induced hypertension by inhibiting group IV cPLA2α (cytosolic phospholipase A2α) activity and production of prohypertensive eicosanoids in female mice. Ang II (700 ng/kg per minute, SC) increased mean arterial blood pressure (BP), systolic and diastolic BP measured by radiotelemetry, renal fibrosis, and reactive oxygen species production in wild-type mice (cPLA2α+/+/Cyp1b1+/+) that were enhanced by ovariectomy and abolished in intact and ovariectomized-cPLA2α−/−/Cyp1b1+/+ mice. Ang II–induced increase in SBP measured by tail-cuff, renal fibrosis, reactive oxygen species production, and cPLA2α activity measured by its phosphorylation in the kidney, and urinary excretion of prostaglandin E2 and thromboxane A2 metabolites were enhanced in ovariectomized-cPLA2α+/+/Cyp1b1+/+ and intact cPLA2α+/+/Cyp1b1−/− mice. 2-Methoxyestradiol and arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid attenuated the Ang II–induced increase in SBP, renal fibrosis, reactive oxygen species production, and urinary excretion of prostaglandin E2, and thromboxane A2 metabolites in ovariectomized-cPLA2α+/+/Cyp1b1+/+ and intact cPLA2α+/+/Cyp1b1−/− mice. Antagonists of prostaglandin E2 and thromboxane A2 receptors EP1 and EP3 and TP, respectively, inhibited Ang II–induced increases in SBP and reactive oxygen species production and renal fibrosis in ovariectomized-cPLA2α+/+/Cyp1b1+/+ and intact cPLA2α+/+/Cyp1b1−/− mice. These data suggest that CYP1B1-generated metabolite 2-methoxyestradiol mitigates Ang II–induced hypertension and renal fibrosis by inhibiting cPLA2α activity, reducing prostaglandin E2, and thromboxane A2 production and stimulating EP1 and EP3 and TP receptors, respectively. Thus, 2-methoxyestradiol and the drugs that selectively block EP1 and EP3 and TP receptors could be useful in treating hypertension and its pathogenesis in females.