Brain-targeted angiotensin-converting enzyme 2 overexpression attenuates neurogenic hypertension by inhibiting cyclooxygenase-mediated inflammation.
Brain-targeted angiotensin-converting enzyme 2 overexpression attenuates neurogenic hypertension by inhibiting cyclooxygenase-mediated inflammation.
复制标题
DOI：
10.1161/hypertensionaha.114.04691
复制
发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Lazartigues E
中科院分区：
文献类型：
--
作者：
Sriramula S;Xia H;Xu P;Lazartigues E
大脑中肾素血管紧张素系统（RAS）、氧化应激和环氧化酶（COX）的过度活性与高血压的发病机制有关。我们之前报道了血管紧张素转换酶2 （ACE2）在大脑中的过度表达可减弱doca盐高血压的发展，doca盐高血压是一种神经源性高血压模型，具有增强的大脑RAS和交感神经活动。为了阐明其中的机制，我们研究了在神经源性高血压中，脑内氧化应激、丝裂原激活的蛋白激酶信号和环氧化酶（COX）激活是否受到ACE2的调节。doca盐高压显著增加了Nox-2（+61±5%）、Nox-4（+50±13%）和硝基酪氨酸（+89±32%）的表达，降低了抗氧化酶、过氧化氢酶（- 29±4%）和SOD（- 31±7%）的活性，表明非转基因小鼠大脑氧化应激增加。在大脑中过表达ACE2的转基因小鼠中，这种增加的氧化应激被减弱。doca -盐诱导的nNOS表达降低（- 26±7%），eNOS/总eNOS磷酸化（- 30±3%），以及室旁核（PVN）中Akt和ERK1/2磷酸化增强，可被ACE2过表达逆转。此外，ACE2过表达减弱了高血压介导的PVN中COX-1和COX-2基因和蛋白表达的增加。此外，大脑中COX-1或COX-2的基因沉默，减少了小胶质细胞的激活并伴有神经炎症，最终减轻了doca盐高血压。总之，这些数据提供了脑ACE2过表达减少氧化应激和cox介导的神经炎症，改善抗氧化和一氧化氮信号，从而减轻神经源性高血压的发展的证据。
Overactivity of the renin angiotensin system (RAS), oxidative stress, and cyclooxygenases (COX) in the brain are implicated in the pathogenesis of hypertension. We previously reported that Angiotensin-Converting Enzyme 2 (ACE2) overexpression in the brain attenuates the development of DOCA-salt hypertension, a neurogenic hypertension model with enhanced brain RAS and sympathetic activity. To elucidate the mechanisms involved, we investigated whether oxidative stress, mitogen activated protein kinase signaling and cyclooxygenase (COX) activation in the brain are modulated by ACE2 in neurogenic hypertension. DOCA-salt hypertension significantly increased expression of Nox-2 (+61 ±5 %), Nox-4 (+50 ±13 %) and nitrotyrosine (+89 ±32 %) and reduced activity of the antioxidant enzymes, catalase (−29 ±4 %) and SOD (−31 ±7 %), indicating increased oxidative stress in the brain of non-transgenic mice. This increased oxidative stress was attenuated in transgenic mice overexpressing ACE2 in the brain. DOCA-salt-induced reduction of nNOS expression (−26 ±7 %) and phosphorylated eNOS/total eNOS (−30 ±3 %), and enhanced phosphorylation of Akt and ERK1/2 in the paraventricular nucleus (PVN), were reversed by ACE2 overexpression. In addition, ACE2 overexpression blunted the hypertension-mediated increase in gene and protein expression of COX-1 and COX-2 in the PVN. Furthermore, gene silencing of either COX-1 or COX-2 in the brain, reduced microglial activation and accompanied neuro-inflammation, ultimately attenuating DOCA-salt hypertension. Together, these data provide evidence that brain ACE2 overexpression reduces oxidative stress and COX-mediated neuro-inflammation, improves anti-oxidant and nitric oxide signaling, and thereby attenuates the development of neurogenic hypertension.