From the Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis (B.L.J., L.W.G., A.K.P., N.S.K., A.M.E., X.R.F., K.U.M.); and Laboratory of Metabolism, National Cancer Institute, Bethesda, MD (F.J.G.).
Hypertension. 2014 Jul;64(1):134-40. doi: 10.1161/HYPERTENSIONAHA.114.03275. Epub 2014 Apr 28.
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.
为了确定细胞色素 P450（CYP）1B1 在血管紧张素 II（Ang II）诱导的高血压性别差异中的作用，雌性 Cyp1b1(+/+) 和 Cyp1b1(-/-) 小鼠接受 Ang II（700ng/kg/min）或载体输注，同时进行或不进行卵巢切除术。此外，用 CYP1B1 抑制剂 2,3',4,5'-四甲氧基二苯乙烯（TMS；300μg/kg，腹腔注射，每三天一次）和 17-β 雌二醇代谢物 2-羟基雌二醇（2-OHE）、4-OHE 或 2-甲氧基雌二醇（1.5mg/kg/天，腹腔注射，持续 2 周）处理小鼠，并测量收缩压（SBP）。Ang II 引起的 SBP 升高在 Cyp1b1(-/-) 小鼠中比 Cyp1b1(+/+) 小鼠更为显著（119±3-171±11 与 120±4-149±4mmHg；P<0.05）。Ang II 导致 Cyp1b1(-/-) 小鼠的心血管重塑和内皮功能障碍，并增加血管反应性和氧化应激，但在 Cyp1b1(+/+) 小鼠中则没有。在 Cyp1b1(+/+) 小鼠中，卵巢切除术和 TMS 增强了 Ang II 引起的 SBP 升高，但在 Cyp1b1(-/-) 小鼠中则没有。2-OHE 并未改变 Cyp1b1(+/+) 小鼠中 Ang II 引起的 SBP 升高，但最小化了 Cyp1b1(-/-) 小鼠中的升高，而 4-OHE 增强了 Cyp1b1(+/+) 小鼠中 Ang II 引起的 SBP 升高，但未改变 Cyp1b1(-/-) 小鼠中升高的 SBP。2-OHE 衍生的儿茶酚-O-甲基转移酶代谢物 2-甲氧基雌二醇抑制 Cyp1b1(-/-) 小鼠中 Ang II 引起的 SBP 升高。Ang II 增加 Cyp1b1(+/+) 小鼠而不是 Cyp1b1(-/-) 小鼠的血浆 2-甲氧基雌二醇水平，并增加 Cyp1b1(-/-) 小鼠而不是 Cyp1b1(+/+) 小鼠的心肌细胞外信号调节激酶 1/2、p38 丝裂原活化蛋白激酶、c-Src 和 Akt 的活性。这些数据表明，CYP1B1 可预防雌性小鼠中 Ang II 诱导的高血压和相关心血管变化，这很可能是通过抑制氧化应激和这些信号分子的活性来介导的。
