Abstract 15979: Restoration of NADH/NAD Ratio Delays Pressure Overload-Induced Cardiac Dysfunction via Regulation of Mitochondrial Protein Acetylation and Permeability Transition
We previously showed that impaired mitochondrial function due to Complex I (C-I) deficiency (by cardiac-specific deletion of Ndufs4, KO) caused a higher NADH/NAD ratio, increased protein acetylation and sensitivity of permeability transition (mPTP) in mitochondria. KO has normal cardiac function when unstressed but develops accelerated heart failure after aortic constriction (TAC). To test whether normalization of NAD redox balance improves cardiac function after TAC, control (Con) and KO mice were subject to sham/TAC surgeries, and treated with a NAD precursor, nicotinamide mononucleotide (NMN, 50 mg/kg) or vehicle (Veh) for 4 weeks. NMN decreased NADH/NAD ratio, protein acetylation, and mPTP sensitivity in KO mitochondria, suggesting a causal relationship among the NAD redox balance, protein acetylation and mPTP function. NMN improved cardiac function in KO mice as assessed by echocardiography (Fractional Shortening, FS, TAC-Veh/NMN: 13±2/31±5 %, n=7-9, p<0.05, Sham: 51±2 %), reduced LV dilation (LVID;d TAC-Veh/NMN: 4.7±0.3/3.9±0.3 mm, p<0.05, Sham: 3.3±0.1 mm) and prevented lung edema (Wet/Dry TAC-Veh/NMN: 5.1±0.1/4.7±0.2, p<0.05, Sham: 4.5±0.1). NMN also recuperated cardiac function in Con-TAC mice (FS, Veh/NMN: 28±4/39±4 %, n=5-8, p<0.05, Sham: 49±2 %; LVID;d Veh/NMN: 4.0±0.3/3.4±0.2 mm, p<0.05, Sham: 3.3±0.2 mm). Cardiac hypertrophy assessed by heart weight to tibia length ratio (HW/TL) was reduced by NMN in both Con-TAC (Veh/NMN: 11.0±0.3/9.1±0.8 mg/mm, p<0.05, Sham: 6.7±0.4 mg/mm) and KO-TAC mice (Veh/NMN: 14.6±1.3/11.1±1.2 mg/mm, p<0.05, Sham: 6.5±0.2 mg/mm). Prolonged opening of mPTP leads to cell death and heart failure progression. Cardiac mitochondria from Con-TAC showed more sensitive mPTP and increased protein acetylation, compared to that from Con-sham. NMN decreased protein acetylation and normalized mPTP sensitivity in mitochondria from Con-TAC. In summary, we show that restoring NAD redox balance decreases protein acetylation and mPTP sensitivity in mitochondria and improves cardiac function in both control and C-I deficient hearts after TAC. These results identify a mechanistic link between impaired mitochondrial function and the development of heart failure, and suggest a potential therapeutic target.
- © 2013 by American Heart Association, Inc.