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Updated: May 18, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Impaired transcriptional activity of Nrf2 in age-related myocardial oxidative stress is reversible by moderate
Sellamuthu S Gounder1, Sankaranarayanan Kannan, Dinesh Devadoss
1Divisions of Cardiology and Pulmonary, Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
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.
Insights
Aging impairs heart antioxidant defenses, increasing cardiovascular disease risk. Moderate exercise training (MET) enhances nuclear erythroid 2 p45-related factor 2 (Nrf2) signaling in aging hearts, restoring antioxidant function and combating oxidative stress.
Area of Science:
- Cardiovascular Physiology
- Aging Research
- Oxidative Stress Biology
Background:
- Aging increases reactive oxygen/nitrogen species (ROS/RNS) in cardiomyocytes, leading to contractile dysfunction and cardiac abnormalities.
- Impaired nuclear erythroid 2 p45-related factor 2 (Nrf2) antioxidant pathways are characteristic of the aging heart, contrasting with young hearts where acute exercise stress (AES) activates Nrf2 signaling.
- Aging hearts exhibit significant oxidative stress compared to younger hearts.
Purpose of the Study:
- To investigate the age-dependent regulation of Nrf2-antioxidant mechanisms and redox homeostasis in mouse hearts.
- To determine the impact of exercise on these age-dependent changes.
- To explore if exercise can mitigate age-induced oxidative stress in the myocardium.
Main Methods:
- Comparison of young and aged mouse hearts under different exercise conditions (acute high endurance exercise stress vs. chronic moderate exercise training).
- Measurement of Nrf2 signaling pathway activation and expression of its target antioxidants.
- Assessment of redox homeostasis and susceptibility to oxidative stress.
Main Results:
- Old mice were susceptible to oxidative stress after high endurance exercise stress (EES), with blunted induction of antioxidant response elements (ARE)-antioxidants compared to young mice.
- Chronic moderate exercise training (MET) for 6 weeks significantly improved adaptive redox homeostasis in aged mice.
- MET promoted nuclear Nrf2 levels and target antioxidant induction in aging hearts, approaching levels seen in young mice.
Conclusions:
- Moderate exercise training (MET) can enhance Nrf2 function and endogenous cytoprotective mechanisms in the aging heart.
- MET may combat age-induced ROS/RNS accumulation and protect the myocardium from oxidative stress-related diseases.
- Exercise interventions hold promise for mitigating age-related cardiac dysfunction.
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