Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation
Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation
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DOI：
10.1161/circresaha.107.169110
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发表时间：
2008-03-28
影响因子：
20.1
通讯作者：
Lazartigues, Eric
中科院分区：
文献类型：
--
作者：
Feng, Yumei;Yue, Xinping;Lazartigues, Eric
我们最近报道了在控制心血管功能的脑区存在血管紧张素转换酶（ACE） 2；然而，由于缺乏专门的工具来研究其功能，ACE2在血压调节中的作用仍不清楚。我们假设ACE2可能通过调节其他肾素-血管紧张素系统成分在心血管功能的中枢调节中发挥关键作用。为了验证这一假设，我们制造了一种腺病毒，在增强型绿色荧光蛋白（eGFP）报告基因（Ad-hACE2-eGFP）上游表达人ACE2 cDNA。体外表征表明，受Ad-hACE2-eGFP感染的神经细胞（10 - 100次感染），而非Ad-eGFP（100次感染），表现出剂量依赖性的ACE2表达和活性。此外，在条件培养基中检测到一种活性分泌形式。在体内，Ad-hACE2-eGFP感染（脑室内2 × 10(6)个斑块形成单位）在小鼠皮层下器官中产生时间依赖性表达和活性（在7天达到峰值）。更重要的是，在病毒感染7天后，Ad-hACE2-eGFP处理的小鼠对血管紧张素（Ang） II（脑室内200 pmol）的升压反应与对照组相比显着降低。此外，皮层下器官靶向ACE2过表达显著降低了Ang II介导的饮酒反应。有趣的是，在体外和体内，ACE2过表达与Ang II型1受体表达下调有关。这些数据表明，在皮层下器官中，ACE2过表达至少通过抑制Ang II型1受体的表达而损害Ang II介导的升压和饮酒反应。综上所述，我们的研究结果表明，ACE2在血压和容量稳态的中枢调节中起着关键作用，为高血压和其他心血管疾病的治疗提供了新的靶点。
We recently reported the presence of angiotensin-converting enzyme ( ACE) 2 in brain regions controlling cardiovascular function; however, the role of ACE2 in blood pressure regulation remains unclear because of the lack of specific tools to investigate its function. We hypothesized that ACE2 could play a pivotal role in the central regulation of cardiovascular function by regulating other renin - angiotensin system components. To test this hypothesis, we generated an adenovirus expressing the human ACE2 cDNA upstream of an enhanced green fluorescent protein (eGFP) reporter gene (Ad-hACE2-eGFP). In vitro characterization shows that neuronal cells infected with Ad-hACE2-eGFP ( 10 to 100 multiplicities of infection), but not Ad-eGFP ( 100 multiplicities of infection), exhibit dose-dependent ACE2 expression and activity. In addition, an active secreted form was detected in the conditioned medium. In vivo, Ad-hACE2-eGFP infection (2x10(6) plaque-forming units intracerebroventricularly) produced time-dependent expression and activity ( with a peak at 7 days) in the mouse subfornical organ. More importantly, 7 days after virus infection, the pressor response to angiotensin (Ang) II ( 200 pmol intracerebroventricularly) was significantly reduced in Ad-hACE2-eGFP - treated mice compared with controls. Furthermore, subfornical organ - targeted ACE2 overexpression dramatically reduced the Ang II - mediated drinking response. Interestingly, ACE2 overexpression was associated with downregulation of the Ang II type 1 receptor expression both in vitro and in vivo. These data suggest that ACE2 overexpression in the subfornical organ impairs Ang II - mediated pressor and drinking responses at least by inhibiting the Ang II type 1 receptor expression. Taken together, our results show that ACE2 plays a pivotal role in the central regulation of blood pressure and volume homeostasis, offering a new target for the treatment of hypertension and other cardiovascular diseases.