Abstract
Aging promotes accumulation of reactive oxygen/nitrogen species (ROS/RNS) in cardiomyocytes, which leads to contractile dysfunction and cardiac abnormalities. These changes may contribute to increased cardiovascular disease in the elderly. Inducible antioxidant pathways are regulated by nuclear erythroid 2 p45-related factor 2 (Nrf2) through antioxidant response cis-elements (AREs) and are impaired in the aging heart. Whereas acute exercise stress (AES) activates Nrf2 signaling and promotes myocardial antioxidant function in young mice (∼2 months), aging mouse (>23 months) hearts exhibit significant oxidative stress as compared to those of the young. The purpose of this study was to investigate age-dependent regulation of Nrf2-antioxidant mechanisms and redox homeostasis in mouse hearts and the impact of exercise. Old mice were highly susceptible to oxidative stress following high endurance exercise stress (EES), but demonstrated increased adaptive redox homeostasis after moderate exercise training (MET; 10m/min, for 45 min/day) for ∼6 weeks. Following EES, transcription and protein levels for most of the ARE-antioxidants were increased in young mice but their induction was blunted in aging mice. In contrast, 6-weeks of chronic MET promoted nuclear levels of Nrf2 along with its target antioxidants in the aging heart to near normal levels as seen in young mice. These observations suggest that enhancing Nrf2 function and endogenous cytoprotective mechanisms by MET, may combat age-induced ROS/RNS and protect the myocardium from oxidative stress diseases.
Highlights
Over 75% of the mortality from cardiac diseases occurs among aged patients [1]
Western blot analysis revealed a significant decrease of nuclear erythroid 2 p45-related factor 2 (Nrf2) (1.060.18 vs. 0.3560.12; young vs. old) in the nuclear extracts of myocardium isolated from aged (.23 months) versus young
Abrogation of Nrf2 resulted in a moderate decrease of some myocardial antioxidants in young Nrf2-/- when compared to WT mice (Fig. 2A)
Summary
It has been reported that aging is an independent factor (despite hypertension, hypercholesterolemia, obesity, smoking) that accelerates oxidative stress and cardiovascular diseases [2,3,4,5,6,7]. It is essential to understand the mechanisms by which aging impairs redox homeostasis in the heart, paving the way to develop novel therapeutic interventions. Sustained hemodynamic stress caused by hypertension, diabetes, and myocardial injury, excessive neurohumoral signaling and even high intensity endurance physical activity may induce pathological cardiac hypertrophy and heart failure/sudden death. ROS/RNS and oxidative stress are strongly associated with cardiac hypertrophy and heart failure [3,6,14,15,16,17,20,21,22]
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