Abstract
Sympatho-excitation is an important hallmark in the heart failure (HF) state. It is known that HF is associated with global oxidative stress, which contributes to pathogenesis of sympatho-excitation. Central reactive oxygen species (ROS) accumulate within neurons and evoke alterations in protein function, leading to an enhanced neuronal excitability, thereby evoking the higher level of sympathetic activation in HF. On the other hand, exercise training (ExT) is associated with a reduction of oxidative stress, in part by upregulation of antioxidant enzymes. However, the link between ExT and antioxidants in the brain of animals with HF has not been explored. In this study, we hypothesized ExT enhances transcriptional activation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that modulates a wide array of antioxidant enzyme gene expression, in the rostral ventrolateral medulla (RVLM). Sham and coronary artery ligation-induced HF mice were divided into either sedentary (Sed) or ExT groups. After 6 weeks of treadmill training, maximal exercise tolerance, urinary norepinephrine (NE) and Nrf2 as well as NAD(P)H dehydrogenase [quinone] 1 (NQO1) gene expression were evaluated by real time RT-PCR. We found that: (1) HF mice displayed significantly lower maximal distance than Sham mice, which was improved by ExT (maximal distance: Sham- Sed 255 ± 34 m (n = 6), HF Sed 148 ± 37 (n = 5), HF ExT 304 ± 34 (n = 6), p<0.05 HF Sed vs HF ExT); (2) urinary NE concentration was significantly higher in HF Sed group which was attenuated by ExT (urinary NE: Sham Sed 442 ± 38 (n = 6), HF Sed 596 ± 41 (n = 5), HF ExT 465 ± 38 ng/ml (n = 6), p<0.05); (3) ExT attenuated HF- induced lower Nrf2 and NQO1 gene expression and also upregulated gene expression of these two proteins in Sham mice (Nrf2: Sham Sed 0.92 ± 0.10 (n = 6), Sham ExT 1.32 ± 0.10 (n = 6), HF Sed 0.60 ± 0.11 (n = 5), HF ExT 0.95 (n = 6), p<0.05), (NQO1: Sham Sed 0.98 ± 0.12 (n = 6), sham ExT 1.39 ± 0.12 (n = 6), HF Sed 0.60 ± 0.13 (n = 5), HF ExT 1.07 ± 0.12 (n = 6), p < 0.05). These data suggest that upregulation of Nrf2 gene expression could be a mechanism by which ExT exerts its beneficial effects on sympathetic tone in HF. Further studies are required to investigate how ExT-induced Nrf2 upregulation alters sympathetic nerve activity in HF.