NRNAD+ Repletion Reverses HFpEF by Attenuating Myocardial Metabolic Dysfunction

Fred

NAD+ Repletion Reverses HFpEF by Attenuating Myocardial Metabolic Dysfunction

Post by Fred » Mon Oct 21, 2019 1:22 pm

Background:

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent clinical condition associated with significant morbidity, mortality and health care expenses. Yet, no effective treatment has been identified. We recently demonstrated that concomitant metabolic and hypertensive stress in mice elicited by a combination of high fat diet (HFD) and constitutive nitric oxide synthase inhibition by N[w]-nitro-l-arginine methyl ester (L-NAME) faithfully recapitulates the numerous and myriad features of human HFpEF

Methods: Wild type C57Bl6 mice were fed with HFD and L-NAME via drinking water for 5-8 weeks. Myocardial mitochondrial morphology was assessed by electron microscopy. Mitochondrial function was assessed by measuring oxygen consumption rates using an oxygen electrode. Protein expression and modification were assessed by Western blotting and immunoprecipitation.

Results: Using this novel mouse model, we discovered significant impairment of mitochondrial fatty acid oxidation (FAO) associated with hyperacetylation of key FAO enzymes in HFpEF myocardium. Mechanistically, downregulation of Sirtuin3, the major mitochondrial deacetylase, and deficiency of its co-substrate nicotinamide adenine dinucleotide (NAD+), culminated in mitochondrial protein hyperacetylation. Strikingly, supplementation with nicotinamide riboside (NR), a NAD+ precursor, led to dramatic improvement of mitochondrial function, and importantly, amelioration of the HFpEF phenotype.

Conclusion: In summary, we have unveiled that protein hyperacetylation-mediated mitochondrial dysfunction is a crucial mechanism of HFpEF pathogenesis. This is, to our knowledge, the first study identifying a specific signature of metabolic remodeling in HFpEF heart. We also demonstrated the therapeutic effect of NAD+ repletion in a preclinical HFpEF model. In next steps, confirming this benefit in a clinical trial is warranted.

https://www.ahajournals.org/doi/abs/10. ... _RGqV1IJng&