ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension
ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension
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DOI：
10.1093/cvr/cvr242
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发表时间：
2011-12-01
影响因子：
10.8
通讯作者：
Francis, Joseph
中科院分区：
文献类型：
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作者：
Sriramula, Srinivas;Cardinale, Jeffrey P.;Francis, Joseph
目的血管紧张素II （Ang II）在高血压介导中具有中枢和外周作用，其中下丘脑室旁核（PVN）是一个重要的脑心脏调节中心。血管紧张素转换酶2 （ACE2）已被确定为angii的降压作用的负调节因子。我们实验室最近的研究结果表明，Ang II输注降低了PVN中ACE2的表达。在本研究中，我们假设在PVN中ACE2的过表达将对对抗Ang ii诱导的高血压有有益的作用。方法与结果采用雄性Sprague-Dawley大鼠进行实验。将编码hACE2的腺病毒（Ad-ACE2）双侧显微注射到PVN中，在该区域过表达ACE2。14天后，注射angii （200 ng/kg/min）的大鼠与注射盐水的对照组（162.9 +/- 3.6 vs 102.3 +/- 1.5 mmHg）相比，通过无线电遥测测得的平均动脉压显著升高。双侧PVN显微注射Ad-ACE2可减轻Ang ii诱导的高血压（130.2 +/- 5.7 vs. 162.9 +/- 3.6 mmHg）。过表达ACE2也显著降低了PVN中AT(1)R和ACE的表达，增加了AT(2)R和Mas的表达。此外，在PVN中ACE2的过表达减弱了Ang ii诱导的PVN中促炎细胞因子肿瘤坏死因子-a、白细胞介素(IL)-1 β和IL-6表达的增加。我们的研究结果表明，PVN中促炎细胞因子的衰减与肾素-血管紧张素系统向抗高血压轴（ACE2/Ang-(1-7)/Mas）的转移可能是PVN中ACE2过表达对Ang ii诱导的高血压反应的整体有益作用的原因。
Aims Angiotensin II (Ang II) has been shown to have both central and peripheral effects in mediating hypertension, for which the hypothalamic paraventricular nucleus (PVN) is an important brain cardio-regulatory centre. Angiotensin-converting enzyme 2 (ACE2) has been identified as a negative regulator of the pro-hypertensive actions of Ang II. Recent findings from our laboratory suggest that Ang II infusion decreases ACE2 expression in the PVN. In the present study, we hypothesized that ACE2 overexpression in the PVN will have beneficial effects in counteracting Ang II-induced hypertension.Methods and results Male Sprague-Dawley rats were used in this study. Bilateral microinjection of an adenovirus encoding hACE2 (Ad-ACE2) into the PVN was used to overexpress ACE2 within this region. Mean arterial pressure measured by radiotelemetry was significantly increased after 14 days in Ang II-infused (200 ng/kg/min) rats vs. saline-infused controls (162.9 +/- 3.6 vs. 102.3 +/- 1.5 mmHg). Bilateral PVN microinjection of Ad-ACE2 attenuated this Ang II-induced hypertension (130.2 +/- 5.7 vs. 162.9 +/- 3.6 mmHg). ACE2 overexpression also significantly decreased AT(1)R and ACE expression and increased AT(2)R and Mas expression in the PVN. Additionally, ACE2 overexpression in the PVN attenuated the Ang II-induced increase in the expression of the pro-inflammatory cytokines tumour necrosis factor-a, interleukin (IL)-1 beta and IL-6 in the PVN.Conclusion Our findings suggest that attenuation of pro-inflammatory cytokines in the PVN in combination with the shift of the renin-angiotensin system towards the anti-hypertensive axis (ACE2/Ang-(1-7)/Mas) may be responsible for the overall beneficial effects of ACE2 overexpression in the PVN on the Ang II-induced hypertensive response.