Estrogen Metabolism by Cytochrome P450 1B1 Modulates the Hypertensive Effect of Angiotensin II in Female Mice

Abstract

To determine the role of CYP1B1 in the gender difference in response to Ang II-induced hypertension, female Cyp1b1+/+ and Cyp1b1−/− mice were infused with Ang II (700 ng/kg/min) or vehicle with/without ovariectomy. In addition, mice were treated with the CYP1B1 inhibitor, 2,3′,4,5′-tetramethoxystilbene (TMS, 300 μg/kg, every 3rd day, i.p.), and 17-β-estradiol metabolites, 2-hydroxyestradiol (2-OHE), 4-OHE, or 2-methoxyestradiol (2-MeE2) (1.5 mg/kg/day, i.p., for 2 weeks), and systolic blood pressure (SBP) measured. Ang II increased SBP more in Cyp1b1−/− than in Cyp1b1+/+ mice (119±3 to 171±11 mmHg vs. 120±4 to 149±4 mmHg, P<0.05). Ang II caused cardiovascular remodeling and endothelial dysfunction, and increased vascular reactivity and oxidative stress in Cyp1b1−/− but not Cyp1b1+/+mice. The Ang II-induced increase in SBP was enhanced by ovariectomy and TMS in Cyp1b1+/+ but not 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-MeE2, inhibited Ang II-induced increase in SBP in Cyp1b1−/− mice. Ang II increased plasma levels of 2MeE2 in Cyp1b1+/+ but not 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 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-MeE2-inhibiting oxidative stress and the activity of these signaling molecules.

2-Methoxyestradiol blocks the RhoA/ROCK1 pathway in human aortic smooth muscle cells

“…In support of this concept, we observed that 2-ME, but not H-1152, inhibits PDGF-induced ERK1/2 and Akt phosphorylation and that 2-ME, but not H-1152, downregulates PDGFinduced cyclin D1 and B1 expression. Consistent with our past (4) and present investigations, studies by Jennings et al (17) in mice provide additional evidence that endogenous 2-ME inhibits ERK1/2 and Akt phosphorylation. The results by Jennings et al, along with our findings, suggest that 2-ME, but not H-1152, downregulates the phosphorylation of proteins important for G 0 /G 1 progression.…”

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

“…In contrast, in female mice, the CYP1B1-generated estradiol metabolite 2-methoxyestradiol is protective against Ang II hypertension, and estradiol ameliorates Ang IIeinduced AAA. 59,60 Our preliminary results indicate that CYP1B1 and 2-methoxyestradiol are protective against Ang IIeinduced AAA in female Apoe À/À mice (Thirunavukkarasu and Malik, unpublished work). Therefore, our study has important translational implications and suggests that the development of selective inhibitors of CYP1B1, such as TMS, could be useful in treating AAA associated with increased activity of the renineAng system in males, but could be detrimental in females.…”

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

“…Indeed, miR-27b levels are significantly upregulated by a high-fat diet and hepatic miR-27b and its target genes are inversely altered in a mouse model of dyslipidemia and atherosclerosis (Vickers et al, 2013). Whether CYP1B1 is involved in the latter is unclear, but the enzyme was recently linked with protection against angiotensin II-induced hypertension in female mice (Jennings et al, 2014).…”

“…CYP1B1. This enzyme is again worth mentioning briefly because the sex difference in the hypertensive response to angiotensin II in mice was recently attributed to the differential expression of CYP1B1 (Jennings et al, 2014). Indeed, CYP1B1 as an estrogen-metabolizing enzyme is more highly expressed in female than male mice and angiotensin II caused cardiovascular remodeling and endothelial dysfunction accompanied by oxidative stress in Cyp1b1 2/2 and ovariectomized Cyp1b1 +/+ mice but not in Cyp1b1 +/+ mice.…”