2-Methoxyestradiol Ameliorates Angiotensin II–Induced Hypertension by Inhibiting Cytosolic Phospholipase A(2)α Activity in Female Mice

Song, Chi Young; Singh, Purnima; Motiwala, Mustafa; Shin, Ji Soo; Lew, Jessica; Dutta, Shubha R.; Gonzalez, Frank J.; Bonventre, Joseph V.; Malik, Kafait U.

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 cPLA(2)α (cytosolic phospholipase A(2)α) 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 (cPLA(2)α(+/+)/Cyp1b1(+/+)) that were enhanced by ovariectomy and abolished in intact and ovariectomized-cPLA(2)α(−/−)/Cyp1b1(+/+) mice. Ang II–induced increase in SBP measured by tail-cuff, renal fibrosis, reactive oxygen species production, and cPLA(2)α activity measured by its phosphorylation in the kidney, and urinary excretion of prostaglandin E(2) and thromboxane A(2) metabolites were enhanced in ovariectomized-cPLA(2)α(+/+)/Cyp1b1(+/+) and intact cPLA(2)α(+/+)/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 E(2), and thromboxane A(2) metabolites in ovariectomized-cPLA(2)α(+/+)/Cyp1b1(+/+) and intact cPLA(2)α(+/+)/Cyp1b1(−/−) mice. Antagonists of prostaglandin E(2) and thromboxane A(2) receptors EP1 and EP3 and TP, respectively, inhibited Ang II–induced increases in SBP and reactive oxygen species production and renal fibrosis in ovariectomized-cPLA(2)α(+/+)/Cyp1b1(+/+) and intact cPLA(2)α(+/+)/Cyp1b1(−/−) mice. These data suggest that CYP1B1-generated metabolite 2-methoxyestradiol mitigates Ang II–induced hypertension and renal fibrosis by inhibiting cPLA(2)α activity, reducing prostaglandin E(2), and thromboxane A(2) 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.