Item Type: | Article |
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Title: | NAD(+) repletion reverses heart failure with preserved ejection fraction |
Creators Name: | Tong, D. and Schiattarella, G.G. and Jiang, N. and Altamirano, F. and Szweda, P.A. and Elnwasany, A. and Lee, D.I. and Yoo, H. and Kass, D.A. and Szweda, L.I. and Lavandero, S. and Verdin, E. and 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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