Background:
Radical forms of oxygen and nitrogen species (ROS/RNS) are highly reactive with nucleic acids, proteins and lipids and promote their oxidation. Normally, cellular ROS/RNS concentrations are tightly controlled by the inducible antioxidant system, which is predominantly regulated by the transcription factor Nrf2 (nuclear erythroid-2 like factor-2) and its cytosolic repressor protein, Keap1. We hypothesized that a decrease or an abrogation of Nrf2 impairs cardiac function and induce hypertrophy upon endurance stress in aging heart.
Methods:
Age-matched wild-type (WT) and Nrf2-/- (KO) mice (n=12/gp) at 2 and >20 months were subjected to endurance exercise stress (EES; 20 meter/min, 12% grade) and assessed the activation of Nrf2/ARE-dependent transcriptional mechanisms in the heart. Cardiac hypertrophy was determined by echocardiography, heart/body weight ratio and biochemical/molecular marker analyses.
Results:
Interestingly, both old-WT and Nrf2-/- mice exhibited oxidative stress on EES due to significant decrease or abrogation of Nrf2 nuclear levels, respectively, suggesting that aged-WT is equally susceptible to stress as Nrf2-/- mice. Age-dependent loss of Nrf2 decreased the transcription of Nrf2-dependent antioxidants and thereby elevated ROS levels to cause a more oxidized intracellular environment. Importantly, the loss of Nrf2 induced cardiac hypertrophy upon endurance stress in the aged (>20 mon) mice. At the end of 2-weeks of endurance stress, both the old-WT and Nrf2-/- mice had developed cardiac hypertrophy. Also, qPCR analysis showed significant (p<0.05) upregulation of hypertrophy markers (ANF and BNF) in the old-WT or Nrf2-/- when compared to sedentary WT mice confirmed cardiac hypertrophy due to loss of Nrf2. These results indicate that either a decrease or an abrogation of Nrf2 can increase susceptibility to stress induced hypertrophy in an aging heart.
Conclusions:
We conclude that enhancing protein levels and stability of nuclear Nrf2 could activate the transcription of major antioxidant enzymes and biosynthesis of key antioxidants. Enhancing protective mechanisms against oxidative stress in the elderly is expected to prevent or delay the onset of age-associated cardiac hypertrophy and cardiomyopathy.
Involvement of PPARγ co-activator-1, nuclear respiratory factors 1 and 2, and PPARα in the adaptive response to endurance exercise