Abstract 95: Exercise Training Prevents Attenuation of Nrf2/ARE-Antioxidant Signaling in Aging Myocardium
Background: Aging promotes accumulation of reactive oxygen/nitrogen species (ROS/RNS) in cardiomyocytes, which lead to contractile dysfunction and cardiac abnormalities. These conditions are prominent in elderly human patients with oxidative stress induced CVD due to impaired antioxidant defense. Inducible antioxidant pathways are regulated by nuclear erythroid 2 p45-related factor 2 (Nrf2) through antioxidant response cis-elements (AREs). We find that the Nrf2 levels are impaired in the aging heart. The purpose of this study was to investigate age-dependent regulation of Nrf2-antioxidant mechanisms and redox homeostasis in the heart.
Methods: Age-matched wild-type (WT) and Nrf2-/- (KO) mice at 2 and >20 months were subjected to endurance exercise stress (EES) and assessed the activation of Nrf2/ARE-dependent transcriptional mechanisms in the heart. Myocardial ROS was measured by electron paramagnetic resonance (EPR) analysis.
Results: Our recent findings indicate that acute exercise stress (AES) activates Nrf2 signaling and promotes myocardial antioxidant function in the young (∼2 months) mouse. Whereas aging mice (>20 months) exhibit significant (p<0.05) oxidative stress as compared to hearts of the young. Though aged-mice are highly susceptible to develop oxidative stress (OS) on endurance exercise stress (EES), they slowly become adaptive to maintain redox homeostasis after moderate exercise training (MET; 10-12m/min, for 45 min/day) for ∼6 weeks. While transcription and protein levels for most of the ARE-antioxidants were increased (p<0.05) in young mice, their induction was blunted in aging mice on EES. Taken together, age-related Nrf2 dysfunction exacerbates EES mediated oxidative stress, which is likely to increase the vulnerability of the aging heart to develop hypertension and pressure overload type of diseases. Of note, a 6-weeks of chronic MET promoted nuclear translocation of Nrf2 along with its target antioxidants in the aging heart to near normal levels seen in young mice.
Conclusions: These observations emphasize the importance of enhancing the Nrf2 function and endogenous cytoprotective mechanisms to combat age-induced ROS/RNS and protecting myocardium from oxidative stress diseases.
- © 2012 by American Heart Association, Inc.