Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska.
J Appl Physiol (1985). 2019 Nov 1;127(5):1349-1359. doi: 10.1152/japplphysiol.00469.2019. Epub 2019 Sep 26.
Chronic heart failure (CHF) is associated with global oxidative stress, which contributes to sympathoexcitation. Increased reactive oxygen species in the brain accumulate within neurons and lead to enhanced neuronal excitability. Exercise training (ExT) is associated with a reduction of oxidative stress by upregulation of antioxidant enzymes. The link between ExT and antioxidant enzyme expression in the brain of animals with CHF is not clear. We hypothesized that ExT enhances transcription and translation of the nuclear factor erythroid 2-related factor 2 (Nrf2) gene, a master transcription factor that modulates antioxidant enzyme gene expression, in the rostral ventrolateral medulla (RVLM) of mice with CHF. Mice were divided into the following groups: Sham sedentary (Sham-Sed), Sham-ExT, CHF-Sed, and CHF-ExT. After 8 wk of ExT, we measured Nrf2 and NAD(P)H dehydrogenase [quinone] 1 (NQO-1) message and protein expression along with maximal exercise tolerance and urinary norepinephrine (NE) excretion. We found that Nrf2 and NQO-1 mRNA and protein expression in the RVLM were lower in CHF-Sed mice compared with Sham-Sed. ExT attenuated the CHF-induced reduction of Nrf2 and NQO-1 mRNA and protein expression in the RVLM. NE excretion was higher in CHF-Sed mice compared with Sham-Sed (666.8 ± 79.3 ng/24 h, = 6 vs. 397.8 ± 43.7 ng/24 h, = 0.04). CHF-ExT mice exhibited reduced urinary NE excretion compared with CHF-Sed (360.7 ± 41.7 ng, = 4 vs. 666.8 ± 79.3 ng, = 6; = 0.03). We conclude that ExT-induced upregulation of Nrf2 in the RVLM contributes to the beneficial effects of ExT on sympathetic function in the heart failure state. This study provide evidence for an important role for exercise training in the modulation of antioxidant enzyme production in the rostral ventrolateral medulla (RVLM) in the heart failure state. We show here a correlation between exercise training and the expression of the antioxidant transcription factor Nrf2 in the RVLM. Exercise training reduced sympathetic function (norepinephrine excretion) and upregulated both Nrf2 and the antioxidant enzyme NQO-1. We conclude that Nrf2 in the RVLM may be an important target for controlling sympathetic outflow in heart failure.
慢性心力衰竭（CHF）与全身氧化应激有关，后者导致交感神经兴奋。大脑中活性氧的增加在神经元内积累，导致神经元兴奋性增强。运动训练（ExT）通过上调抗氧化酶来减少氧化应激。CHF 动物的 ExT 与大脑中抗氧化酶表达之间的联系尚不清楚。我们假设 ExT 增强了 CHF 小鼠延髓头端腹外侧区（RVLM）中核因子红细胞 2 相关因子 2（Nrf2）基因的转录和翻译，Nrf2 是调节抗氧化酶基因表达的主要转录因子。小鼠分为以下几组：假手术安静（Sham-Sed）、假手术运动（Sham-ExT）、心力衰竭安静（CHF-Sed）和心力衰竭运动（CHF-ExT）。经过 8 周的 ExT，我们测量了 RVLM 中的 Nrf2 和 NAD（P）H 脱氢酶[醌]1（NQO-1）的 mRNA 和蛋白表达以及最大运动耐力和尿去甲肾上腺素（NE）排泄。我们发现，与 Sham-Sed 相比，CHF-Sed 小鼠的 RVLM 中 Nrf2 和 NQO-1mRNA 和蛋白表达降低。ExT 减弱了 CHF 诱导的 RVLM 中 Nrf2 和 NQO-1mRNA 和蛋白表达的降低。与 Sham-Sed 相比，CHF-Sed 小鼠的尿 NE 排泄量更高（666.8±79.3ng/24h， = 6 与 397.8±43.7ng/24h， = 0.04）。与 CHF-Sed 相比，CHF-ExT 小鼠的尿 NE 排泄量减少（360.7±41.7ng， = 4 与 666.8±79.3ng， = 6； = 0.03）。我们得出结论，ExT 诱导的 RVLM 中 Nrf2 的上调有助于 ExT 对心力衰竭状态下交感神经功能的有益作用。这项研究为运动训练在调节心力衰竭状态下延髓头端腹外侧区（RVLM）抗氧化酶产生中的重要作用提供了证据。我们在这里显示了运动训练与 RVLM 中抗氧化转录因子 Nrf2 表达之间的相关性。运动训练降低了交感神经功能（去甲肾上腺素排泄），并上调了 Nrf2 和抗氧化酶 NQO-1。我们得出结论，RVLM 中的 Nrf2 可能是控制心力衰竭时交感神经输出的重要靶点。
