Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, USA.
Cardiovasc Res. 2011 Dec 1;92(3):401-8. doi: 10.1093/cvr/cvr242. Epub 2011 Sep 27.
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.
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-α, interleukin (IL)-1β and IL-6 in the PVN.
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.
血管紧张素 II（Ang II）已被证明具有介导高血压的中枢和外周作用，其中下丘脑室旁核（PVN）是一个重要的脑心血管调节中心。血管紧张素转换酶 2（ACE2）已被确定为 Ang II 促高血压作用的负调节剂。我们实验室的最近发现表明，Ang II 输注会降低 PVN 中的 ACE2 表达。在本研究中，我们假设 PVN 中的 ACE2 过表达将对抵消 Ang II 诱导的高血压具有有益作用。
本研究使用雄性 Sprague-Dawley 大鼠。使用双侧将编码 hACE2 的腺病毒（Ad-ACE2）微注射到 PVN 中，以在该区域过表达 ACE2。通过无线电遥测测量的平均动脉压在 Ang II 输注（200 ng/kg/min）大鼠中 14 天后显着升高，与盐水输注对照相比（162.9 ± 3.6 对 102.3 ± 1.5 mmHg）。双侧 PVN 微注射 Ad-ACE2 减轻了这种 Ang II 诱导的高血压（130.2 ± 5.7 对 162.9 ± 3.6 mmHg）。ACE2 过表达还显着降低了 PVN 中的 AT(1)R 和 ACE 表达，并增加了 AT(2)R 和 Mas 表达。此外，PVN 中的 ACE2 过表达还减轻了 Ang II 诱导的 PVN 中促炎细胞因子肿瘤坏死因子-α、白细胞介素（IL）-1β 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以及肾素-血管紧张素系统向抗高血压轴（ACE2/Ang-(1-7)/Mas）的转变可能是 ACE2 在 PVN 中过表达对 Ang II 诱导的高血压反应产生整体有益作用的原因。
