Central CYP1B1 (Cytochrome P450 1B1)-Estradiol Metabolite 2-Methoxyestradiol Protects From Hypertension and Neuroinflammation in Female Mice.
Central CYP1B1 (Cytochrome P450 1B1)-Estradiol Metabolite 2-Methoxyestradiol Protects From Hypertension and Neuroinflammation in Female Mice.
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中枢 CYP1B1（细胞色素 P450 1B1）-雌二醇代谢物 2-甲氧基雌二醇可预防雌性小鼠的高血压和神经炎症。
DOI：
10.1161/hypertensionaha.119.14548
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Malik,KafaitU
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作者：
Singh,Purnima;Song,ChiYoung;Dutta,ShubhaRanjan;Gonzalez,FrankJ;Malik,KafaitU
之前，我们发现外周给予2-ME（2-甲氧基雌二醇），一种CYP 1B 1（细胞色素P450 1B 1）-儿茶酚-O-甲基转移酶（COMT），可产生E2（17β-雌二醇）的代谢产物，可保护雌性小鼠免受血管紧张素II诱导的高血压。证明中枢E2抑制血管紧张素II诱导的高血压，以及脑中CYP 1B 1的表达，使我们假设E2-CYP 1B 1在脑中产生代谢物2-ME介导其对雌性小鼠血管紧张素II诱导的高血压的保护作用。为了验证这一假设，我们研究了脑室内（ICV）给予卵巢切除（OVX）-野生型（Cyp 1b 1 +/+）和OVX-Cyp 1b 1 −/−小鼠E2对全身血管紧张素II作用的影响。ICV-E2减弱了血管紧张素II诱导的平均动脉血压升高、压力反射敏感性受损和OVX-Cyp 1b 1 +/+小鼠的交感神经活性，但在ICV注射的短干扰（si）RNA-COMT或OVX-Cyp 1b 1 −/−小鼠中没有。ICV-2-ME减弱了OVX-Cyp 1b 1 −/−小鼠中血管紧张素II诱导的血压升高;这种作用被ICV-siRNA雌激素受体-α（ERα）和G蛋白偶联雌激素受体1（GPER 1）抑制。ICV-E2在OVX-Cyp 1b 1 +/+小鼠中，但在OVX-Cyp 1b 1 −/−小鼠中没有，2-ME在OVX-Cyp 1b 1 −/−小鼠中抑制血管紧张素II诱导的穹窿下器官和室旁核中活性氧产生的增加，小胶质细胞和星形胶质细胞的激活，以及室旁核中的神经炎症。此外，ICV-腺病毒-GFP（绿色荧光蛋白）-CYP 1B 1-短发夹（sh）RNA对Cyp 1b 1 +/+小鼠中枢CYP 1B 1基因的破坏作用升高，而腺病毒-GFP-CYP 1B 1-DNA在室旁核（而非穹隆下器官）的重建作用减弱了Cyp 1b 1 −/−小鼠血管紧张素II诱导的收缩压升高。这些数据表明，E2-CYP 1B 1-COMT产生的代谢产物2-ME（最可能在室旁核中通过雌激素受体-α和GPER 1）可保护雌性小鼠免受血管紧张素II诱导的高血压和神经炎症。
Previously, we showed that peripheral administration of 2-ME (2-methoxyestradiol), a CYP1B1 (cytochrome P450 1B1)-catechol-O-methyltransferase (COMT) generated metabolite of E2 (17β-Estradiol), protects against angiotensin II-induced hypertension in female mice. The demonstration that central E2 inhibits angiotensin II-induced hypertension, together with the expression of CYP1B1 in the brain, led us to hypothesize that E2-CYP1B1 generated metabolite 2-ME in the brain mediates its protective action against angiotensin II-induced hypertension in female mice. To test this hypothesis, we examined the effect of intracerebroventricularly (ICV) administered E2 in ovariectomized (OVX)-wild-type (Cyp1b1+/+) and OVX-Cyp1b1−/−mice on the action of systemic angiotensin II. ICV-E2 attenuated the angiotensin II-induced increase in mean arterial blood pressure, impairment of baroreflex sensitivity, and sympathetic activity in OVX-Cyp1b1+/+but not in ICV-injected short interfering (si)RNA-COMT or OVX-Cyp1b1−/−mice. ICV-2-ME attenuated the angiotensin II-induced increase in blood pressure in OVX-Cyp1b1−/−mice; this effect was inhibited by ICV-siRNA estrogen receptor-α (ERα) and G protein-coupled estrogen receptor 1 (GPER1). ICV-E2 in OVX-Cyp1b1+/+but not in OVX-Cyp1b1−/−mice and 2-ME in the OVX-Cyp1b1−/−inhibited angiotensin II-induced increase in reactive oxygen species production in the subfornical organ and paraventricular nucleus, activation of microglia and astrocyte, and neuroinflammation in paraventricular nucleus. Furthermore, central CYP1B1 gene disruption inCyp1b1+/+mice by ICV-adenovirus-GFP (green fluorescence protein)-CYP1B1-short hairpin (sh)RNA elevated, while reconstitution by adenovirus-GFP-CYP1B1-DNA in the paraventricular nucleus but not in subfornical organ inCyp1b1−/−mice attenuated the angiotensin II-induced increase in systolic blood pressure. These data suggest that E2-CYP1B1-COMT generated metabolite 2-ME, most likely in the paraventricular nucleus via estrogen receptor-α and GPER1, protects against angiotensin II-induced hypertension and neuroinflammation in female mice.