Brain-selective overexpression of human Angiotensin-converting enzyme type 2 attenuates neurogenic hypertension.
Brain-selective overexpression of human Angiotensin-converting enzyme type 2 attenuates neurogenic hypertension.
复制标题
DOI：
10.1161/circresaha.109.208645
复制
发表时间：
2010-02-05
影响因子：
20.1
通讯作者：
Lazartigues E
中科院分区：
文献类型：
--
作者：
Feng Y;Xia H;Cai Y;Halabi CM;Becker LK;Santos RA;Speth RC;Sigmund CD;Lazartigues E
血管紧张素转换酶2 （Angiotensin converting enzyme 2, ACE2）是脑肾素-血管紧张素系统的新成员，它可能被过度活跃的肾素-血管紧张素系统激活。利用一种新的转基因小鼠模型，阐明中枢ACE2在突触蛋白启动子控制下的作用，从而在中枢神经系统中实现神经元靶向表达。Syn-hACE2 （SA）转基因小鼠在整个大脑中表现出高的hACE2蛋白表达和活性。基线血流动力学参数（遥测）、自主神经功能和自发压力反射敏感性（SBRS）在SA小鼠和非转基因窝鼠（NT）之间无显著差异。脑靶向ACE2过表达可减轻神经源性高血压的发展（Ang II输注：600 ng/kg）。min/14天)和相关的SBRS和副交感神经张力的降低。阻断Ang-(1-7)受体（D-ala7-Ang-(1-7)）可逆转这种通过ACE2过表达预防高血压的作用；600 ng / kg.min)。SA小鼠脑AT2/AT1和Mas/AT1受体比值显著升高。注射Ang- ii后仍保持较高水平，但阻断Ang-(1-7)受体后显著降低。ACE2过表达导致脑内NOS和NO水平升高，抑制了ang - ii介导的BP调节区NOS表达的下降。ACE2过表达部分通过阻止SBRS和副交感神经张力的降低来减轻神经源性高血压的发展。这些保护作用可能是由ma和AT2受体上调引起的脑内NO释放增强介导的。综上所述;我们的数据强调了中枢ACE2的代偿作用及其作为神经源性高血压治疗靶点的潜在益处。
Angiotensin converting enzyme 2 (ACE2) is a new member of the brain renin-angiotensin system, that might be activated by an overactive renin-angiotensin system. To clarify the role of central ACE2 using a new transgenic mouse model with hACE2 under the control of a synapsin promoter, allowing neuron-targeted expression in the central nervous system. Syn-hACE2 (SA) transgenic mice exhibit high hACE2 protein expression and activity throughout the brain. Baseline hemodynamic parameters (telemetry), autonomic function and spontaneous baroreflex sensitivity (SBRS) were not significantly different between SA mice and non-transgenic littermates (NT). Brain-targeted ACE2 over-expression attenuated the development of neurogenic hypertension (Ang II infusion: 600 ng/kg.min/14 days) and the associated reduction of both SBRS and parasympathetic tone. This prevention of hypertension by ACE2 over-expression was reversed by blockade of the Ang-(1–7) receptor (D-ala7-Ang-(1–7); 600 ng/kg.min). Brain AT2/AT1 and Mas/AT1 receptor ratios were significantly increased in SA mice. They remained higher following Ang-II infusion but were dramatically reduced after Ang-(1–7) receptor blockade. ACE2 over-expression resulted in increased NOS and NO levels in the brain, and prevented the Ang-II-mediated decrease in NOS expression in regions modulating BP regulation. ACE2 over-expression attenuates the development of neurogenic hypertension partially by preventing the decrease in both SBRS and parasympathetic tone. These protective effects might be mediated by enhanced NO release in the brain resulting from Mas and AT2 receptor up-regulation. Taken together; our data highlight the compensatory role of central ACE2 and its potential benefits as a therapeutic target for neurogenic hypertension.