Abstract 417: Targeting the NAD/NADH Ratio for Heart Failure Therapy

Energy deficiency and mitochondrial dysfunction are strongly implicated in the development of heart failure (HF). Yet, the exact mechanisms remain poorly understood. Recently, a causal relationship between loss of cardiac NAD(H) homeostasis and mitochondrial dysfunction have been proposed in HF. A number of studies have demonstrated the benefit of raising NAD levels prior to or at the time of inducing heart failure, but it is unknown whether this strategy benefits hearts with established or pre-existing dysfunction. Therefore, in the present study we increased NAD level in wild-type (WT) mice after pathological hypertrophy and dysfunction were induced by transverse aortic constriction (TAC) surgery. WT mice were treated daily for six-weeks with nicotinamide riboside (NR) starting four-weeks after TAC. The NR treatments significantly elevated NAD level in the TAC hearts (3.1 fold, n=4) compared to vehicle treated mice, accompanied by an improvement in fractional shortening (FS) (sham vehicle 51%±2% vs TAC Vehicle 31%±3% vs TAC NR 43%±5%, n=4 each group). Most evidence thus far suggest the benefit of raising NAD level in the failing heart involves activation of sirtuin 3 (Sirt3), a NAD dependent deacylase. We hypothesize there are Sirt3 independent mechanisms that are activated by increasing NAD levels to benefit the failing heart. To test this hypothesis, we treated Sirt3 deficient (Sirt3-/-) mice with NR starting four-weeks after TAC surgery and extended the study to ten-weeks post TAC. NR treatments elevated cardiac NAD level (2.9-fold, n=4) compared to vehicle treated controls. This correlated with lowered global protein acetylation in the hearts and an improvement in FS (sham vehicle 50%±5% vs TAC vehicle 24%±6% vs TAC NR 41%±8%). We also looked at mitochondrial function in Sirt3-/- mice ten-weeks after TAC ± NR treatments and observed an increase in state 3 ADP-stimulated respiration in the NR treated Sirt3-/- mice (sham vehicle 183±17 vs TAC vehicle 103±23 vs TAC NR 127±21 nmol/min/mg). These findings suggest increasing NAD can improve cardiac function through Sirt3 independent mechanisms including one that enhances mitochondrial respiration. Further elucidation of these mechanisms could identify novel NAD sensitive therapeutic targets.