From the Department of Pharmacology, Addiction Science, and Toxicology, College of Medicine, University of Tennessee Health Science Center, Memphis (P.S., S.R.D., C.Y.S.).
Laboratory of Metabolism, National Cancer Institute, Bethesda, MD (F.J.G.).
Hypertension. 2020 Sep;76(3):1006-1018. doi: 10.1161/HYPERTENSIONAHA.120.15567. Epub 2020 Aug 3.
Previously, we showed that peripheral administration of 6β-hydroxytestosterone, a CYP1B1 (cytochrome P450 1B1)-generated metabolite of testosterone, promotes angiotensin II-induced hypertension in male mice. However, the site of action and the underlying mechanism by which 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension is not known. Angiotensin II increases blood pressure by its central action, and CYP1B1 is expressed in the brain. This study was conducted to determine whether testosterone-CYP1B1 generated metabolite 6β-hydroxytestosterone locally in the brain promotes the effect of systemic angiotensin II to produce hypertension in male mice. Central CYP1B1 knockdown in wild-type () mice by intracerebroventricular-adenovirus-GFP (green fluorescence protein)-CYP1B1-short hairpin (sh)RNA attenuated, whereas reconstitution of CYP1B1 by adenovirus-GFP-CYP1B1-DNA in the paraventricular nucleus but not in subfornical organ in mice restored angiotensin II-induced increase in systolic blood pressure measured by tail-cuff. Intracerebroventricular-testosterone in orchidectomized (Orchi)- but not in Orchi-, and intracerebroventricular-6β-hydroxytestosterone in the Orchi- mice restored the angiotensin II-induced: (1) increase in mean arterial pressure measured by radiotelemetry, and autonomic imbalance; (2) reactive oxygen species production in the subfornical organ and paraventricular nucleus; (3) activation of microglia and astrocyte, and neuroinflammation in the paraventricular nucleus. The effect of intracerebroventricular-6β-hydroxytestosterone to restore the angiotensin II-induced increase in mean arterial pressure and autonomic imbalance in Orchi- mice was inhibited by intracerebroventricular-small interfering (si)RNA-androgen receptor (AR) and GPRC6A (G protein-coupled receptor C6A). These data suggest that testosterone-CYP1B1-generated metabolite 6β-hydroxytestosterone, most likely in the paraventricular nucleus via AR and GPRC6A, contributes to angiotensin II-induced hypertension and neuroinflammation in male mice.
先前，我们发现外周给予睾酮的 CYP1B1（细胞色素 P450 1B1）代谢产物 6β-羟基睾酮可促进雄性小鼠的血管紧张素 II 诱导的高血压。然而，6β-羟基睾酮在血管紧张素 II 诱导的高血压中的作用部位和潜在机制尚不清楚。血管紧张素 II 通过中枢作用增加血压，而 CYP1B1 在大脑中表达。本研究旨在确定大脑中局部产生的睾酮-CYP1B1 代谢产物 6β-羟基睾酮是否促进全身血管紧张素 II 的作用，从而导致雄性小鼠发生高血压。通过脑室内给予腺病毒-GFP（绿色荧光蛋白）-CYP1B1-shRNA 来抑制野生型（）小鼠的中枢 CYP1B1，而在小鼠的室旁核中通过腺病毒-GFP-CYP1B1-DNA 重建 CYP1B1 可恢复血管紧张素 II 引起的收缩压升高，这是通过尾套测量的。在去势（Orchi）-但不在 Orchi-的雄性小鼠中，脑室内给予睾酮可恢复血管紧张素 II 引起的：（1）通过无线电遥测测量的平均动脉压升高和自主神经失衡；（2）在室旁核和穹窿下器官中产生的活性氧；（3）室旁核中小胶质细胞和星形胶质细胞的激活以及神经炎症。脑室内给予 6β-羟基睾酮可恢复 Orchi-雄性小鼠血管紧张素 II 诱导的平均动脉压升高和自主神经失衡，这一作用可被脑室内小干扰（si）RNA-雄激素受体（AR）和 GPRC6A（G 蛋白偶联受体 C6A）抑制。这些数据表明，睾酮-CYP1B1 生成的代谢产物 6β-羟基睾酮，很可能通过 AR 和 GPRC6A 在室旁核中，有助于雄性小鼠的血管紧张素 II 诱导的高血压和神经炎症。
