Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA.
J Appl Physiol (1985). 2010 Apr;108(4):923-32. doi: 10.1152/japplphysiol.00840.2009. Epub 2010 Jan 21.
Exercise training (EX) normalizes sympathetic outflow and plasma ANG II in chronic heart failure (CHF). The central mechanisms by which EX reduces this sympathoexcitatory state are unclear, but EX may alter components of the brain renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) may mediate an increase in sympathetic nerve activity (SNA). ACE2 metabolizes ANG II to ANG-(1-7), which may have antagonistic effects to ANG II. Little is known concerning the regulation of ACE and ACE2 in the brain and the effect of EX on these enzymes, especially in the CHF state. This study aimed to investigate the effects of EX on the regulation of ACE and ACE2 in the brain in an animal model of CHF. We hypothesized that the ratio of ACE to ACE2 would increase in CHF and would be reduced by EX. Experiments were performed on New Zealand White rabbits divided into the following groups: sham, sham + EX, CHF, and CHF + EX (n = 5 rabbits/group). The cortex, cerebellum, medulla, hypothalamus, paraventricular nucleus (PVN), nucleus tractus solitarii (NTS), and rostral ventrolateral medulla (RVLM) were analyzed. ACE protein and mRNA expression in the cerebellum, medulla, hypothalamus, PVN, NTS, and RVLM were significantly upregulated in CHF rabbits (ratio of ACE to GAPDH: 0.3 +/- 0.03 to 0.8 +/- 0.10 in the RVLM, P < 0.05). EX normalized this upregulation compared with CHF (0.8 +/- 0.1 to 0.4 +/- 0.1 in the RVLM). ACE2 protein and mRNA expression decreased in CHF (ratio of ACE2 to GAPDH: 0.3 +/- 0.02 to 0.1 +/- 0.01 in the RVLM). EX increased ACE2 expression compared with CHF (0.1 +/- 0.01 to 0.8 +/- 0.1 in the RVLM). ACE2 was present in the cytoplasm of neurons and ACE in endothelial cells. These data suggest that the activation of the central RAS in animals with CHF involves an imbalance of ACE and ACE2 in regions of the brain that regulate autonomic function and that EX can reverse this imbalance.
运动训练（EX）可使慢性心力衰竭（CHF）患者的交感神经输出和血浆血管紧张素 II（ANG II）恢复正常。EX 降低这种交感兴奋状态的中枢机制尚不清楚，但 EX 可能改变脑肾素-血管紧张素系统（RAS）的组成部分。血管紧张素转换酶（ACE）可能介导交感神经活性（SNA）的增加。ACE2 将 ANG II 代谢为 ANG-（1-7），其可能对 ANG II 具有拮抗作用。关于 ACE 和 ACE2 在大脑中的调节以及 EX 对这些酶的影响，特别是在 CHF 状态下，知之甚少。本研究旨在探讨 EX 对 CHF 动物模型中大脑中 ACE 和 ACE2 调节的影响。我们假设 ACE 与 ACE2 的比值在 CHF 中会增加，并会因 EX 而降低。实验在分为以下几组的新西兰白兔上进行：假手术组、假手术+EX 组、CHF 组和 CHF+EX 组（每组 5 只兔子）。分析皮质、小脑、延髓、下丘脑、室旁核（PVN）、孤束核（NTS）和延髓头端腹外侧区（RVLM）。CHF 兔小脑、延髓、下丘脑、PVN、NTS 和 RVLM 中的 ACE 蛋白和 mRNA 表达显著上调（ACE 与 GAPDH 的比值：RVLM 中为 0.3 +/- 0.03 至 0.8 +/- 0.10，P < 0.05）。EX 使这种上调与 CHF 相比趋于正常（RVLM 中为 0.8 +/- 0.1 至 0.4 +/- 0.1）。CHF 时 ACE2 蛋白和 mRNA 表达下降（ACE2 与 GAPDH 的比值：RVLM 中为 0.3 +/- 0.02 至 0.1 +/- 0.01）。EX 与 CHF 相比增加了 ACE2 的表达（RVLM 中为 0.1 +/- 0.01 至 0.8 +/- 0.1）。ACE2 存在于神经元的细胞质中，ACE 存在于血管内皮细胞中。这些数据表明，CHF 动物中枢 RAS 的激活涉及调节自主功能的大脑区域中 ACE 和 ACE2 的不平衡，而 EX 可以逆转这种不平衡。
