2-Methoxyestradiol Ameliorates Angiotensin II–Induced Hypertension by Inhibiting Cytosolic Phospholipase A2α Activity in Female Mice. Issue 5 (November 2021)

• Record Type: Journal Article
• Authors: Song, Chi Young; Singh, Purnima; Motiwala, Mustafa; Shin, Ji Soo; Lew, Jessica; Dutta, Shubha R.; Gonzalez, Frank J.; Bonventre, Joseph V.; Malik, Kafait U.
• Is Part Of: Hypertension. Volume 78:Issue 5(2021)
• Publication Date: 2021-11
• Subjects: blood pressure -- fibrosis -- ovariectomy -- phosphorylation -- renin; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.121.18181
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : 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 cPLA2 α (cytosolic phospholipase A2 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 cPLA2 α activity measured by its phosphorylation in the kidney, and urinary excretion of prostaglandin E2 and thromboxane A2 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 E2, and thromboxane A2 metabolites in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /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- 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 cPLA2 α 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. Abstract : Supplemental Digital Content is available in the text.