Abstract 568: Loss of Nrf2 Exacerbates Cardiac Hypertrophy and Dysfunction in Response to Pressure-Overload
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional effector of antioxidant systems in response to cellular stress. Importantly, although oxidative stress is a critical factor contributing to the pathogenesis of left ventricular (LV) hypertrophy and failure, the importance of Nrf2 in the pathogenesis of LV remodeling is unknown. We hypothesized that Nrf2 induction is a cardioprotective response during pressure-overload hypertrophy that attenuates maladaptive remodeling and delays the transition to failure. Wild type (WT, n = 11) and Nrf2 knockout (KO, n = 10) mice were subjected to ascending aorta banding (AAB) to induce pressure-overload LV hypertrophy or sham operation and followed for 4 weeks. There was no baseline cardiac phenotype in the Nrf2 KO hearts. Four weeks post-AAB, mean aortic pressure gradients by Doppler echocardiography from WT and KO banded mice were similar (50 – 60 mmHg) indicating equivalence of mechanical load. As compared to WT sham, WT AAB hearts displayed significant (p < 0.05) LV/myocyte hypertrophy and myocardial fibrosis, but with preserved LV size and systolic function by echocardiography and no change in normalized right ventricular (RV) or lung weights. In contrast, despite similar degrees of pressure-overload, Nrf2 KO AAB hearts displayed significantly (p < 0.05 vs WT AAB) exaggerated LV hypertrophy (LV/BW ratio 9.0 ± 0.4 vs 6.7 ± 0.7 mg/g; myocyte area 457 ± 117 vs 339 ± 76 μm2), fibrosis (% Masson’s staining 4.5 ± 0.9 vs 2.3 ± 0.30), and significant LV chamber dilatation and dysfunction (fractional shortening 41±5 vs. 48 ±4). Moreover, these hearts exhibited significantly (p < 0.05 vs. WT AAB) increased RV/BW ratio (1.3 ± 0.3 vs 0.6 ± 0.4 mg/g), and atrial, lung, and liver weights (mg/g: atria/BW 0.9 ± 0.3 vs 0.5 ± 0.1; lung/BW 23.0 ± 1.8 vs 11.4 ± 4.0; liver/BW 74.4 ± 0.41 vs 44.1 ± 0.3) all indicating early transition to LV failure with pulmonary/systemic congestion and RV hypertrophy.
Conclusion: Nrf2 is cardioprotective during LV pressure-overload, serving to maintain LV systolic function, attenuate pathological hypertrophy and fibrosis, and delay the transition to cardiac failure. Augmentation of the Nrf2 axis may constitute a novel therapeutic approach to mitigate detrimental LV hypertrophy.