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Estrogen metabolism by cytochrome P450 1B1 modulates the hypertensive effect of angiotensin II in female mice.

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 ?g/kg IP, every third day), and 17-? 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.

SUBMITTER: Jennings BL

PROVIDER: S-EPMC4065791 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Estrogen metabolism by cytochrome P450 1B1 modulates the hypertensive effect of angiotensin II in female mice.

Jennings Brett L BL George L Watson LW Pingili Ajeeth K AK Khan Nayaab S NS Estes Anne M AM Fang Xiao R XR Gonzalez Frank J FJ Malik Kafait U KU

Hypertension (Dallas, Tex. : 1979) 20140428 1

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, ...[more]

PMID: 24777982

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Project description:Previously, we showed that Cyp1b1 gene disruption minimizes angiotensin II-induced hypertension and associated pathophysiological changes in male mice. This study was conducted to test the hypothesis that cytochrome P450 1B1-generated metabolites of testosterone, 6β-hydroxytestosterone and 16α-hydroxytestosterone, contribute to angiotensin II-induced hypertension and its pathogenesis. Angiotensin II infusion for 2 weeks increased cardiac cytochrome P450 1B1 activity and plasma levels of 6β-hydroxytestosterone, but not 16α-hydroxytestosterone, in Cyp1b1(+/+) mice without altering Cyp1b1 gene expression; these effects of angiotensin II were not observed in Cyp1b1(-/-) mice. Angiotensin II-induced increase in systolic blood pressure and associated cardiac hypertrophy, and fibrosis, measured by intracardiac accumulation of α-smooth muscle actin, collagen, and transforming growth factor-β, and increased nicotinamide adenine dinucleotide phosphate oxidase activity and production of reactive oxygen species; these changes were minimized in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice, and restored by treatment with 6β-hydroxytestoterone. In Cyp1b1(+/+) mice, 6β-hydroxytestosterone did not alter the angiotensin II-induced increase in systolic blood pressure; the basal systolic blood pressure was also not affected by this agent in either genotype. Angiotensin II or castration did not alter cardiac, angiotensin II type 1 receptor, angiotensin-converting enzyme, Mas receptor, or androgen receptor mRNA levels in Cyp1b1(+/+) or in Cyp1b1(-/-) mice. These data suggest that the testosterone metabolite, 6β-hydroxytestosterone, contributes to angiotensin II-induced hypertension and associated cardiac pathogenesis in male mice, most probably by acting as a permissive factor. Moreover, cytochrome P450 1B1 could serve as a novel target for developing agents for treating renin-angiotensin and testosterone-dependent hypertension and associated pathogenesis in males.

Project description:This manuscript summarizes our recent progress in examine the CYP1A1 and CYP1B1 as well as a number of nuclear receptors in the female genital and colorectal tissues of human and pigtailed macaque. Understanding the nuclear receptor mediated regulation of CYP1A1 and 1B1 expression in these tissues is necessary for identifying cancer risk factors and developing CYP1A1/1B1-targeted anti-cancer therapeutics. However, there is a lack of systematic and comparative analysis of the expression profile of CYP1A1, 1B1 and NRs in the female genital and colorectal tissues of human and clinically relevant animal models. The current study aims to fill this gap. We found CYP1A1, CYP1B1 and a number of nuclear receptors were expressed in the female genital and colorectal tissues of human and macaque. However, the mRNA level and protein localization of these CYP enzymes and NRs depended on the type of tissue examined. Cytochrome P450 (CYP) 1A1 and CYP1B1 activate hormonal and environmental procarcinogens, and are associated with carcinogenesis in female genital and colorectal tissues. Understanding the nuclear receptor (NR) mediated regulation of CYP expression in these tissues is necessary for identifying cancer risk factors and developing CYP1A1/1B1-targeted anti-cancer therapeutics. The study aims to analyze the expression profile of CYP1A1, 1B1 and NRs in the female genital and colorectal tissues of human and pigtailed macaques. We found that compared to the liver, human CYP1A1 mRNA level in the genital and colorectal tissues was significantly lower, while the CYP1B1 level was significantly higher. CYP1A1 protein was mainly localized in the plasma membrane of the uterine and endocervical epithelial cells. The CYP1B1 protein was concentrated in the nucleus of genital and colorectal tissues. Fourteen NRs in the genital tract and 12 NRs in colorectal tissue were expressed at levels similar to or higher than the liver. The expression and localization of CYP1A1, CYP1B1, and NRs in macaque tissues were usually comparable to those of human tissues. In addition, menopause did not significantly alter the ectocervical mRNA levels of CYP1A1, CYP1B1, or NRs.

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Estrogen metabolism by cytochrome P450 1B1 modulates the hypertensive effect of angiotensin II in female mice.

Publications

Estrogen metabolism by cytochrome P450 1B1 modulates the hypertensive effect of angiotensin II in female mice.

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