NAD(+) repletion reverses heart failure with preserved ejection fraction

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Item Type:	Article
Title:	NAD(+) repletion reverses heart failure with preserved ejection fraction
Creators Name:	Tong, D., Schiattarella, G.G., Jiang, N., Altamirano, F., Szweda, P.A., Elnwasany, A., Lee, D.I., Yoo, H., Kass, D.A., Szweda, L.I., Lavandero, S., Verdin, E., Gillette, T.G. and Hill, J.A.
Abstract:	RATIONALE: Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. We recently demonstrated in mice that a combination of metabolic and hypertensive stress recapitulates key features of human HFpEF. OBJECTIVE: Using this novel preclinical HFpEF model, we set out to define and manipulate metabolic dysregulations occurring in HFpEF myocardium. METHODS AND RESULTS: We observed impairment in mitochondrial fatty acid oxidation associated with hyperacetylation of key enzymes in the pathway. Down-regulation of sirtuin 3 and deficiency of NAD(+) secondary to an impaired NAD(+) salvage pathway contribute to this mitochondrial protein hyperacetylation. Impaired expression of genes involved in NAD(+) biosynthesis was confirmed in cardiac tissue from HFpEF patients. Supplementing HFpEF mice with nicotinamide riboside or a direct activator of NAD(+) biosynthesis led to improvement in mitochondrial function and amelioration of the HFpEF phenotype. CONCLUSIONS: Collectively, these studies demonstrate that HFpEF is associated with myocardial mitochondrial dysfunction and unveil NAD(+) repletion as a promising therapeutic approach in the syndrome.
Keywords:	Heart Failure with Preserved Ejection Fraction, Mitochondria, Acetylation, Cardiomyopathy, Heart Failure, Animals, Mice
Source:	Circulation Research
ISSN:	0009-7330
Publisher:	American Heart Association
Volume:	128
Number:	11
Page Range:	1629-1641
Date:	28 May 2021
Additional Information:	Copyright © 2021 American Heart Association, Inc.
Official Publication:	https://doi.org/10.1161/CIRCRESAHA.120.317046
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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