Catechol-O-Methyltransferase Deficiency Leads to Hypersensitivity of the Pressor Response Against Angiotensin II
Catechol-O-Methyltransferase Deficiency Leads to Hypersensitivity of the Pressor Response Against Angiotensin II
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DOI：
10.1161/hypertensionaha.117.09247
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发表时间：
2017
期刊：
影响因子：
8.3
通讯作者：
Norikazu Ueki;K. Kanasaki;M. Kanasaki;S. Takeda;D. Koya
中科院分区：
文献类型：
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作者：
Norikazu Ueki;K. Kanasaki;M. Kanasaki;S. Takeda;D. Koya
儿茶酚-O-甲基转移酶（COMT）将2-羟基雌二醇代谢为2-甲氧基雌二醇（2-ME）; COMT缺乏与男性高血压和先兆子痫相关，先兆子痫是一种与血管紧张素II（Ang II）升压反应超敏反应相关的疾病。在这里，我们发现，COMT缺乏可以解释对血管紧张素II的升压反应在小鼠中的超敏反应，因为缺乏2-ME依赖性抑制血管紧张素II受体1型（AT 1 R）。雄性C57 BL/6小鼠接受COMT抑制剂（COMTi：25 mg/kg/天）或油（对照）4周，最后3周有或没有低剂量Ang II输注（ANGII：70 ng/kg/分钟）。Ang II灌注小鼠用2-ME（10 ng/d）或溶剂处理最后1周。我们获得了以下实验组：对照组、ANGII组、COMTi组、COMTi+ANGII组和COMTi+ANGII+2-ME组。ANGII和COMTi均未表现出收缩压的显著变化。与ANGII或COMTi相比，COMTi+ANGII显示出显着更高的收缩压、蛋白尿和肾小球内皮增生; 2-ME使这些变化正常化。在COMT小干扰RNA处理的小鼠中观察到类似的表型。在COMT缺陷小鼠的主动脉中，AT 1 R表达增加; 2-ME抑制AT 1 R表达。2-ME表现出过氧化物酶体增殖物激活受体激动剂活性在体外和离体血浆从怀孕的雌性小鼠以及。在体外，2-ME抑制基础和血管紧张素II诱导的AT 1 R水平的过氧化物酶体增殖物激活受体依赖的方式。2-ME通过其过氧化物酶体增殖物激活受体活性抑制AT 1 R来对抗COMT缺乏相关的高血压疾病。
Catechol-O-methyltransferase (COMT) metabolizes 2-hydroxyestradiol into 2-methoxyestradiol (2-ME); COMT deficiency has shown to be associated with hypertension in men and preeclampsia, the disease associated with hypersensitivity of pressor response against angiotensin II (Ang II). Here, we found that COMT deficiency could explain the hypersensitivity of pressor response against Ang II in mice because of the lack of 2-ME–dependent suppression of angiotensin II receptor type 1 (AT1R). Male C57BL/6 mice were subjected to COMT inhibitor (COMTi: 25 mg/kg per day) or oil (control) for 4 weeks, with or without low-dose Ang II infusion (ANGII: 70 ng/kg per minute) for the last 3 weeks. The Ang II–infused mice were treated with 2-ME (10 ng/d) or vehicle for the last 1 week. We obtained the following experimental groups: control, ANGII, COMTi, COMTi+ANGII, and COMTi+ANGII+2-ME. We performed similar experiments using the in vivo administration of small interfering RNA of COMT instead of COMTi. Neither ANGII nor COMTi exhibited significant alterations in systolic blood pressure. Compared with ANGII or COMTi, COMTi+ANGII displayed significantly higher systolic blood pressure, albuminuria, and glomerular endotheliosis; 2-ME normalized such alterations. Similar phenotypes were observed in COMT small interfering RNA–treated mice. In the aorta of COMT-deficient mice, AT1R expression was increased; 2-ME suppressed AT1R expression. The 2-ME exhibited peroxisome proliferator–activated receptor agonistic activity in vitro and ex vivo plasma from pregnant female mice as well. In vitro, 2-ME suppressed both basal and Ang II–induced AT1R levels in a peroxisome proliferator–activated receptor –dependent manner. The 2-ME is relevant to combat COMT deficiency–associated hypertensive disorders via suppression of AT1R by its peroxisome proliferator–activated receptor activity.