Abstract 4364396: Modulation of Myocardial Histidyl Dipeptide Synthesis Alters Cardiac Function During Heart Failure

Abstract

Background: Cardiomyocytes produce histidyl dipeptides such as carnosine (β-alanyl-L-histidine) and anserine (β-alanyl-N π -methylhistidine) via carnosine synthase (CARNS) that are known to conjugate with toxic lipid peroxidation products and buffer intracellular pH. Our lab has shown these dipeptides are decreased in failing hearts and oral supplementation of the carnosine precursor β-alanine to heart failure mice restores carnosine levels and improves cardiac function. However, β-alanine also increases carnosine in other carnosine-producing tissues, such as skeletal muscle. Therefore, effects of cardiac-specific changes to carnosine levels on cardiac function during heart failure remain unknown. Hypothesis: Cardiac-specific overexpression of CARNS will attenuate, while cardiac-specific deletion will exacerbate cardiac function during heart failure. Methods: 12-week-old male wild type (WT), cardiac-specific CARNS overexpressing (CS-Tg), and null (CS-KO) mice were subjected to transverse aortic constriction (TAC) surgery. CS-KO mice were generated by breeding Carns fl/fl with aMHC-mER-Cre-mER (MCM) mice. MCM + offspring were injected with 4-OH-tamoxifen for 5 days followed by a 1-week washout before surgery. Changes in cardiac function and gene expression were evaluated by echocardiography and RT-qPCR respectively. Results: In CS-KO mice hearts, CARNS protein levels were decreased ~2-3-fold, and carnosine levels were decreased ~4-fold (80±8 pmol/mg protein vs fl/fl: 367±26 pmol/mg protein, p<0.05) compared with tamoxifen-injected Carns fl/fl . 2 weeks post-TAC, CS-KO mice showed decreased EF (28±3% vs fl/fl: 43±4%, p<0.05), increased EDV (77±6 μL vs fl/fl: 50±6 μL, p<0.05), and increased ESV (56±6 μL vs fl/fl: 30±5 μL, p<0.05) compared with tamoxifen injected Carns fl/fl . Conversely, 8 weeks post-TAC, compared to WT TAC controls, CS-Tg TAC mice showed improved EF (43±15% vs WT: 21±15%, p<0.05), LVID at diastole (4.4±0.4 vs WT: 5.0±0.3, p<0.05) and systole (3.5±0.7 vs WT: 4.4±0.5, p<0.05), and ~2-fold decrease in hypertrophic markers ( Nppa, Myh7 ). Conclusion: Cardiac-specific deletion of CARNS exacerbates while overexpression attenuates cardiac function and pathological remodeling during heart failure, suggesting anti-remodeling benefits of myocardial carnosine under heart failure conditions. Carnosine is well tolerated and readily available over the counter, thus representing a safe, efficacious, and novel pathway for therapeutic intervention in failing hearts.