Abstract 16369: Nrf2 Deficiency Exacerbates Pathological Cardiac Remodeling in Response to Resistance Exercise
Introduction: Myocardial remodeling resulting in ventricular hypertrophy and dysfunction are either strongly correlated or causally linked to chronic redox imbalance. Nuclear erythroid-2 like factor-2 (Nrf2), a master transcriptional regulator plays a major role in cellular redox homeostasis. Here we investigated whether age-associated decline in Nrf2 is causal to stress induced cardiac remodeling and heart failure.
Hypothesis: We hypothesize that genetic ablation or age-dependent decline of Nrf2 impairs myocardial redox state and induces pathological ventricular hypertrophy upon resistance exercise (RE).
Methods and results: Age and sex matched WT and Nrf2-null mice (>22 months; n=6/gp.) were subjected to RE stress for 6 Weeks (25 meter/min, 12% grade) and cardiac functions were assessed by echocardiography and electrocardiogram. Biochemical, cellular and molecular indices related to redox and myocardial structural and functional remodeling were also analyzed.
Results: Pre- and post- echocardiography analyses in response to RE indicated progressive cardiac hypertrophy in both WT and Nrf2-null mice on aging. Interestingly, the degree of cardiac remodeling was significantly higher in Nrf2-null when compared to WT mice. Dramatic increase in ejection fraction, cardiac output and R amplitude (V) suggesting that Nrf2 deficiency cause pathological remodeling. Transcriptional signatures of hypertrophy (Anf, Bnf and β-Mhc) were significantly (p<0.05) upregulated in Nrf2-null versus WT mice in response to RE. Under sedentary state, loss of Nrf2 was associated with significant downregulation of antioxidant genes (Nqo1, Ho1, Gclm, Cat and Gst-α). After RE, the transcript levels of Gclc, Nqo1, Gsr and Gst-α were profoundly diminished in Nrf2-null versus WT mice. Further, significant increase in DMPO-adduct coupled with the decreased myocardial glutathione levels illustrates oxidative stress in Nrf2-null mouse after RE. Further, increased accumulation of HNE-protein adducts and ubiquitinated proteins, known markers of proteasome inhibition were noted in Nrf2-null mice after RE.
Conclusions: Our findings indicate that loss of Nrf2 could induce pathological ventricular remodeling and cardiac dysfunction over aging.
Author Disclosures: G. Shanmugam: None. M. Narasimhan: None. R.L. Conley: None. R. Radhakrishnan: None. N. Rajasekaran: None.
- © 2016 by American Heart Association, Inc.