2-Methoxyestradiol Reduces Angiotensin II–Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice. Issue 6 (June 2017)

• Record Type: Journal Article
• Authors: Pingili, Ajeeth K.; Davidge, Karen N.; Thirunavukkarasu, Shyamala; Khan, Nayaab S.; Katsurada, Akemi; Majid, Dewan S.A.; Gonzalez, Frank J.; Navar, L. Gabriel; Malik, Kafait U.
• Is Part Of: Hypertension. Volume 69:Issue 6(2017:Jun.)
• Publication Date: 2017-06
• Subjects: 2-methoxyestradiol -- CYP1B1 -- end-organ damage -- hypertension -- urinary angiotensinogen; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.117.09175
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : Cytochrome P450 1B1 protects against angiotensin II (Ang II)–induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine whether 2-methoxyestradiol ameliorates Ang II–induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1 −/−, ovariectomized female, and Cyp1b1 +/+ male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 hours. 2-Methoxyestradiol reduced Ang II–induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1 −/− and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II–induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1 +/+ male mice. Treatment with 2-methoxyestradiol attenuated Ang II–induced end-organ damage in intact Cyp1b1 −/− and ovariectomized Cyp1b1 +/+ and Cyp1b1 −/− female mice and Cyp1b1 +/+ male mice. 2-Methoxyestradiol mitigated Ang II–induced increase in urinary excretion of angiotensinogen in intact Cyp1b1 −/− and ovariectomized Cyp1b1 +/+ and Cyp1b1 −/− female mice but not in Cyp1b1 +/+ male mice. The G protein–coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II–induced increases in blood pressure and renal function in Cyp1b1 +/+ female mice. These data suggest that 2-methoxyestradiol reduces Ang II–induced hypertension and associated end-organ damage in intact Cyp1b1 −/−, ovariectomized Cyp1b1 +/+ and Cyp1b1 −/− female mice, and Cyp1b1 +/+ male mice independent of G protein–coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males. Abstract : Supplemental Digital Content is available in the text.