In:
Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 64, No. 1 ( 2014-07), p. 134-140
Abstract:
To determine the role of cytochrome P450 (CYP) 1B1 in the sex difference in response to angiotensin II (Ang II)–induced hypertension, female Cyp1b1 +/+ and Cyp1b1 −/− mice were infused with Ang II (700 ng/kg per minute) or vehicle with or without ovariectomy. In addition, mice were treated with the CYP1B1 inhibitor, 2,3′,4,5′-tetramethoxystilbene (TMS; 300 μg/kg IP, every third day), and 17-β estradiol metabolites, 2-hydroxyestradiol (2-OHE), 4-OHE, or 2-methoxyestradiol (1.5 mg/kg per day IP, for 2 weeks) and systolic blood pressure (SBP) measured. Ang II increased SBP more in Cyp1b1 −/− than in Cyp1b1 +/+ mice (119±3–171±11 versus 120±4–149±4 mm Hg; P 〈 0.05). Ang II caused cardiovascular remodeling and endothelial dysfunction and increased vascular reactivity and oxidative stress in Cyp1b1 −/− but not in Cyp1b1 +/+ mice. The Ang II–induced increase in SBP was enhanced by ovariectomy and TMS in Cyp1b1 +/+ but not in Cyp1b1 −/− mice. 2-OHE did not alter Ang II–induced increase in SBP in Cyp1b1 +/+ mice but minimized it in Cyp1b1 −/− mice, whereas 4-OHE enhanced Ang II–induced increase in SBP in Cyp1b1 +/+ mice but did not alter the increased SBP in Cyp1b1 −/− mice. 2-OHE–derived catechol-O-methyltransferase metabolite, 2-methoxyestradiol, inhibited Ang II–induced increase in SBP in Cyp1b1 −/− mice. Ang II increased plasma levels of 2-methoxyestradiol in Cyp1b1 +/+ but not in Cyp1b1 −/− mice and increased activity of cardiac extracellular signal–regulated kinase 1/2, p38 mitogen-activated kinase, c-Src, and Akt in Cyp1b1 −/− but not in Cyp1b1 +/+ mice. These data suggest that CYP1B1 protects against Ang II–induced hypertension and associated cardiovascular changes in female mice, most likely mediated by 2-methoxyestradiol–inhibiting oxidative stress and the activity of these signaling molecules.
Type of Medium:
Online Resource
ISSN:
0194-911X
,
1524-4563
DOI:
10.1161/HYPERTENSIONAHA.114.03275
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
2094210-2
