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, n = 6 vs. 397.8 ± 43.7 ng/24 h, P = 0.04). CHF-ExT mice exhibited reduced urinary NE excretion compared with CHF-Sed (360.7 ± 41.7 ng, n = 4 vs. 666.8 ± 79.3 ng, n = 6; P = 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.NEW & NOTEWORTHY 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.