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.
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Authors | Brett L Jennings, L Watson George, Ajeeth K Pingili, Nayaab S Khan, Anne M Estes, Xiao R Fang, Frank J Gonzalez, Kafait U Malik |
Journal | Hypertension (Dallas, Tex. : 1979)
(Hypertension)
Vol. 64
Issue 1
Pg. 134-40
(Jul 2014)
ISSN: 1524-4563 [Electronic] United States |
PMID | 24777982
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 American Heart Association, Inc. |
Chemical References |
- Angiotensin II
- Estradiol
- Aryl Hydrocarbon Hydroxylases
- Cyp1b1 protein, mouse
- Cytochrome P-450 CYP1B1
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Topics |
- Angiotensin II
- Animals
- Aryl Hydrocarbon Hydroxylases
(genetics, metabolism)
- Blood Pressure
(drug effects, physiology)
- Cytochrome P-450 CYP1B1
- Estradiol
(metabolism)
- Female
- Heart
(drug effects)
- Hypertension
(chemically induced, metabolism)
- Mice
- Mice, Knockout
- Myocardium
(metabolism)
- Oxidative Stress
(drug effects)
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