Proteomics

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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): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Mark Larance  

LAB HEAD: Mark Larance

PROVIDER: PXD033027 | Pride | 2024-08-09

REPOSITORIES: pride

Dataset's files

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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
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Publications


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

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