Abstract 539: Buthionine Sulfoximine (BSO) Prevents Reductive Stress-induced Pathological Hypertrophic Cardiomyopathy

Background: Chronic reductive stress (RS) induces pathological cardiac remodeling and diastolic dysfunction. Here, we hypothesized that preventing RS via glutathione (GSH) depletion, through selective inhibition of γ-glutamyl cysteine ligase (γGCL), mitigates cardiac pathology in cRS mice. Methods: Cardiac-specific constitutively active Nrf2 TG-mice (α-MHc-caNrf2-TG), at 6 weeks of age, were administered with buthionine sulfoximine (BSO; 5.0 mM/Kg; daily for 16-weeks). At the end of 22 weeks, cardiac structure and function (systole & diastole using echocardiography), myocardial redox state, levels of ROS (using dihydroethidium (DHE) fluorescence), and antioxidant proteome were assessed in TG mice treated with PBS or BSO and compared with the age matched NTG littermates (n=6/group). Results: While the TG mice experiencing RS (GSH; 426.3±22.55 vs. 141.8±3.9 & GSH/GSSG; 61.04±5.4 vs. 23.27±1.3 in TG vs. NTG), this was significantly curtailed in BSO-treated TG mice (GSH 161.8±12.6 & GSH/GSSG; 25.1±4.3). This was coupled with the normal cardiac functions (EF; ~53% & MV E/A; 1.57) in the BSO-treated TG when compared to TG mice experiencing a hyper systolic function (>80% ejection fraction) with decreased cardiac volume and diastolic dysfunction with restricted filling (MV E/A ratio; >3.0), Of note, BSO treatment did not alter the protein levels of antioxidants (i.e. GCLC, GCLM, NQO1 and CAT), but only depleted the GSH pool (via inhibiting GCL activity) and restored the basal ROS signaling in the myocardium. Moreover, the BSO-treated TG mice did not develop cardiac hypertrophy, which was assessed by heart weight/body weight ratio, qPCR-based gene expression for hypertrophy ( Anf, Bnf, α-MHc and β-Mhc ). Conclusion: Our results suggest that pharmacological manipulation of myocardial redox and repletion of basal ROS signaling prevented RS-mediated pathological processes and rescued the cardiac structure and function.