Background:
Heart failure is a leading health problem with over 500,000 new cases and 275,000 deaths annually in the United States. Recent reports indicate that atrial fibrillation (AF) is linked to various forms of ventricular dysfunction (VD). Over 2 million Americans have AF, which is more prevalent in people over 65 years of age. However, the molecular “cause and effect” relationship between AF and VD has not been elucidated. We hypothesize that abrogation of nuclear erythroid-2 like factor-2 (Nrf2), a master antioxidant transcriptional regulator, induces atrial remodeling and fibrillation on aging.
Methods:
Age and sex matched WT and Nrf2-/- mice were used in this study. Atrial mass, remodeling, antioxidants and molecular redox signaling were studied at 2 and >20 months of age. Echocardiography, immunoblotting, quantitative real-time PCR and immunofluorescence (fibrosis) analyses were performed in the atrial tissue.
Results:
At 2 months of age, WT and Nrf2-/- mice had comparable levels of ROS in the atrium. On aging, the ROS levels were significantly increased in atria of Nrf2-
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when compared to wild-type (WT) mice at 20 months of age. While decreased Nrf2-antioxidant signaling in response to increased ROS generation in atria of Nrf2-
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mice was observed, ventricular function appeared to be normal at 20 months of age. However, upon endurance exercise stress (EES), hypertrophy markers including ANF, BNF, PLN and SERCA2A were significantly (p<0.05) altered in Nrf2-
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when compared to age-matched WT mice. Further, activation of fibrotic process was evident in the Nrf2-
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mouse atrium as indicated by significantly (p<0.05) increased markers of tissue remodeling (i.e. MMP2/9) on aging. These results indicating an early onset of atrial hypertrophy/remodeling due to age-induced oxidative stress, which cause AF in Nrf2-
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mice. Age-dependent decline in Nrf2 and sustained progression of AF could lead to ventricular dysfunction and heart failure.
Conclusion:
Our findings indicate that atria are primary targets to age-associated oxidative stress and exhibit fibrosis, which promotes atrial fibrillation and remodeling. Thus, activation of Nrf2 signaling to prevent oxidative stress could be a potential therapeutic target for AF.
P4478Cardiac specific overexpression of activated protein-1 transcription factor JunD protects against oxidative stress and left ventricular dysfunction in the diabetic heart
