Dataset Information

Prophylactic or therapeutic NAD+ repletion can prevent or rescue HFpEF, but dietary intervention and weight loss cannot

ABSTRACT: Left ventricular (LV) diastolic dysfunction is a hallmark of Heart Failure with preserved Ejection Fraction (HFpEF), an escalating global health challenge. We demonstrated selective depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) and the rate-limiting enzyme of the NAD+ biosynthetic salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), in human myocardium with LV diastolic dysfunction. We showed that NAD+ can be replenished in human myocardium with diastolic impairment ex vivo, despite reduced NAMPT expression. In a murine model of HFpEF [a combination exposure to high-fat diet (HFD) and L-NG-Nitro arginine methyl ester (L-NAME)], we compared the benefits of NAD+ precursor supplementation versus dietary intervention. We tested NAD+ repletion by nicotinamide riboside (NR) supplementation using two clinically-relevant strategies: 1) Prophylactic NR repletion before HFpEF onset, and 2) Therapeutic NR repletion after the development of HFpEF. We found that dietary intervention (replacement of HFD and L-NAME with healthy diet) restored myocardial insulin-dependent glucose uptake and glycolysis but did not rescue HFpEF. In contrast, both NAD+ repletion strategies prevented or rescued HFpEF, respectively, plausibly due to restoration of myocardial iron homeostasis, recoupling of glycolysis to the TCA cycle, and upregulation of antioxidant defense.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Mark Larance

LAB HEAD: Mark Larance

PROVIDER: PXD033027 | Pride | 2024-08-09

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20210316_HFX4_ML_RL_EXP1_109_1.raw	Raw
	20210316_HFX4_ML_RL_EXP1_109_2.raw	Raw
	20210316_HFX4_ML_RL_EXP1_109_3.raw	Raw
	20210316_HFX4_ML_RL_EXP1_109_4.raw	Raw
	20210316_HFX4_ML_RL_EXP1_110_1.raw	Raw

Items per page:

1 - 5 of 107

Publications

The Efficacy of Risk Factor Modification Compared to NAD+ Repletion in Diastolic Heart Failure.

Koay Yen Chin YC Liu Ren Ping RP McIntosh Bailey B Vigder Niv N Lauren Serlin S Bai Angela Yu AY Tomita Saki S Li Desmond D Harney Dylan D Hunter Benjamin B Zhang Yunwei Y Yang Jean J Bannon Paul P Philp Ashleigh A Philp Andrew A Kaye David M DM Larance Mark M Lal Sean S O'Sullivan John F JF

JACC. Basic to translational science 20240320 6

Heart failure (HF) with left ventricular diastolic dysfunction is a growing global concern. This study evaluated myocardial oxidized nicotinamide adenine dinucleotide (NAD+) levels in human systolic and diastolic HF and in a murine model of HF with preserved ejection fraction, exploring NAD+ repletion as therapy. We quantified myocardial NAD+ and nicotinamide phosphoribosyltransferase levels, assessing restoration with nicotinamide riboside (NR). Findings show si ...[more]

PMID: 39070276

Similar Datasets

Project description:BACKGROUND: Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes HFD+L-NAME (ad libitum high-fat diet and 0.5% N[ω]-nitro-L-arginine methyl ester), we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to HFD+L-NAME. METHODS: Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein Nnt (nicotinamide nucleotide transhydrogenase), we established an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of HFD+L-NAME. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt−/−) Nnt in the C57BL/6N background were challenged with HFD+L-NAME for 9 weeks (N=6–10). RESULTS: Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via noninvasive echocardiographic quantification of early diastolic pulse-wave velocity (E) to mitral annular velocity (e′) ratio (E/e′) (42.8 versus 21.5, P=1.2×10−10), E/A (early-to-late mitral inflow velocity ratio) (2.3 versus 1.4, P=4.1×10−2), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, P=5.1×10−3), and myocardial fibrosis (P=2.3×10−2). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD+ (P=8.4×10−3) and a 38.8% reduction in the ratio of reduced-to-oxidized glutathione (GSH: GSSG, P=2.6×10−2) among Nnt+/+ mice after HFD+L-NAME feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling in myocardial fibrosis. CONCLUSIONS: Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.

Dataset Information

Prophylactic or therapeutic NAD+ repletion can prevent or rescue HFpEF, but dietary intervention and weight loss cannot

Dataset's files

Publications

The Efficacy of Risk Factor Modification Compared to NAD<sup>+</sup> Repletion in Diastolic Heart Failure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets