Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, 68198-5850, USA.
Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2402-12. doi: 10.1152/ajpheart.00330.2011. Epub 2011 Sep 30.
Angiotensin (ANG)-converting enzyme (ACE)2 in brain regions such as the paraventricular nucleus (PVN) controlling cardiovascular function may be involved in the regulation of sympathetic outflow in chronic heart failure (CHF). The purpose of this study was to determine if ACE2 plays a role in the central regulation of sympathetic outflow by regulating neuronal nitric oxide (NO) synthase (nNOS) in the PVN. We investigated ACE2 and nNOS expression within the PVN of rats with CHF. We then determined the effects of ACE2 gene transfer in the PVN on the contribution of NO-mediated sympathoinhibition in rats with CHF. The results showed that there were decreased expressions for ACE2, the ANG-(1-7) receptor, and nNOS within the PVN of rats with CHF. After the application of adenovirus vectors encoding ACE2 (AdACE2) into the PVN, the increased expression of ACE2 in the PVN was confirmed by Western blot analysis. AdACE2 transfection significantly increased nNOS protein levels (change of 50 ± 5%) in the PVN of CHF rats. In anesthetized rats, AdACE2 treatment attenuated the responses of renal sympathetic nerve activity (RSNA), mean arterial pressure, and heart rate to the NOS inhibitor N-monomethyl-L-arginine in rats with CHF (RSNA: 28 ± 3% vs. 16 ± 3%, P < 0.05) compared with CHF + AdEGFP group. Furthermore, neuronal NG-108 cells incubated with increasing doses of AdACE2 showed a dose-dependent increase in nNOS protein expression (60% at the highest dose). Taken together, our data highlight the importance of increased expression and subsequent interaction of ACE2 and nNOS within the PVN, leading to a reduction in sympathetic outflow in the CHF condition.
脑内的血管紧张素转换酶 2（ACE2）在控制心血管功能的室旁核（PVN）等区域可能参与了慢性心力衰竭（CHF）时交感神经传出的调节。本研究旨在探讨 ACE2 是否通过调节 PVN 中的神经元型一氧化氮合酶（nNOS）在中枢调节交感神经传出中发挥作用。我们检测了 CHF 大鼠 PVN 中的 ACE2 和 nNOS 表达。随后，我们观察了在 PVN 中进行 ACE2 基因转移对 CHF 大鼠中 NO 介导的交感抑制作用的影响。结果显示，CHF 大鼠的 PVN 中 ACE2、血管紧张素（1-7）受体和 nNOS 的表达减少。Western blot 分析证实，将 ACE2 编码的腺病毒载体（AdACE2）应用于 PVN 后，PVN 中 ACE2 的表达增加。AdACE2 转染显著增加了 CHF 大鼠 PVN 中的 nNOS 蛋白水平（变化 50±5%）。在麻醉大鼠中，与 CHF+AdEGFP 组相比，AdACE2 治疗可减弱 NOS 抑制剂 N-单甲基-L-精氨酸引起的肾交感神经活动（RSNA）、平均动脉压和心率的反应（RSNA：28±3%比 16±3%，P<0.05）。此外，NG-108 神经元细胞孵育于不同剂量的 AdACE2 后，nNOS 蛋白表达呈剂量依赖性增加（最高剂量时增加 60%）。综上，我们的数据强调了 ACE2 和 nNOS 在 PVN 中的表达增加及其随后相互作用的重要性，导致 CHF 状态下交感神经传出减少。
