Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy
Background—Myocardial metabolic impairment is a major feature in chronic heart failure (HF). As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, NAD+ is emerging as a metabolic target in a number of diseases including HF. Little is known on mechanisms regulating homeostasis of NAD+ in the failing heart.
Methods—To explore possible alterations of NAD+ homeostasis in the failing heart, we quantified expression of NAD+ biosynthetic enzymes in human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by SRF transcription factor depletion in the heart (SRFHKO) or of cardiac hypertrophy triggered by transverse aorta constriction (TAC). We studied the impact of NAD+ precursor supplementation on cardiac function in both mouse models.
Results—We observed a 30% loss in levels of NAD+ in the murine failing heart of both DCM and TAC mice that was accompanied by a decrease in expression of the NAMPT enzyme that recycles the nicotinamide (NAM) precursor whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside (NR) precursor is increased, to a higher level in the DCM (40 fold) than in TAC (4 fold). This shift was also observed in human failing heart biopsies compared to non-failing controls. We show that the Nmrk2 gene is an AMPK and PPARalpha responsive gene that is activated by energy stress and NAD+ depletion in isolated rat cardiomyocytes. NR efficiently rescues NAD+ synthesis in response to FK866-mediated inhibition of NAMPT and stimulates glycolysis in cardiomyocytes. Accordingly, we show that NR supplementation in food attenuates the development of HF in mice, more robustly in DCM, and partially after TAC, by stabilizing myocardial NAD+ levels in the failing heart. NR treatment also robustly increases the myocardial levels of three metabolites, nicotinic acid adenine dinucleotide, methyl-NAM and N1-Methyl-4-pyridone-5-carboxamide, which can be used as validation biomarkers for the treatment.
Conclusions—The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of HF notably in the context of DCM, a disease with few therapeutic options.
- nicotinamide riboside
- serum response factor
- energy metabolism
- nicotinamide adenine dinucleotide
- dilated cardiomyopathy
- heart failure
- transcriptional regulation
- Received October 23, 2016.
- Revision received October 27, 2017.
- Accepted November 6, 2017.