Abstract 16960: Sodium Sulfide Therapy Attenuates Cardiac Dysfunction in the Setting of Heart Failure in a Nrf2-Dependent Manner
Background: Nuclear-factor-E2-related factor 2 (Nrf2), a member of the NF-E2 family of nuclear basic leucine zipper transcription factors, regulates the gene expression of enzymes that serve to detoxify pro-oxidative stressors. Recent studies also indicated that Nrf2 regulates the expression of the subunits of the 20S proteasome. Here, we tested the hypothesis that Nrf2 signaling mediates the cardioprotective effects of sodium sulfide (Na2S) therapy in the setting of ischemic-induced heart failure.
Methods and Results: Heart failure was induced by subjecting Nrf2-deficient (Nrf2 KO; C57BL/6 background) and wild-type (WT) control mice to 60 min of myocardial ischemia followed by reperfusion (R) for 4 wks. Nrf2 KO and WT mice received either saline (Veh) or Na2S (100 μ g/kg) at the time of R followed by daily injections for the first 7 days of R. Echocardiography analysis revealed that after 4 wks of R all groups displayed significant LV dilation and severe cardiac dysfunction with the Nrf2 KO mice displaying exacerbated dysfunction compared to the WT mice. Treatment with Na2S significantly reduced the degree of dilation and improved LV ejection fraction in the WT mice but failed to provide protection in the Nrf2 KO mice. Western blot analysis of heart tissue (n=4/group) revealed that 7 days of Na2S therapy (Na2S Sham) significantly (p<0.05 vs. Sham) increased the expression of the 20S proteasome β1 subunit (PSMB1). These studies also revealed that the expression of PSMB1 was slightly increased following the induction of heart failure and that treatment with Na2S (I/R + Na2S) augmented this increase (p<0.05 vs. Sham and I/R + Veh). Additionally, a reduction in the expression of the ER-stress protein, GRP94, was observed in the Na2S-treated hearts when compared to Veh-treated hearts (p<0.001).
Conclusion: These findings provide important information that Nrf2 plays a protective role in the setting of heart failure and mediates the cardioprotective effects of Na2S therapy.
- © 2012 by American Heart Association, Inc.