Abstract P2001: Nicotinamide Riboside the New Promising Drug of Myocardial Infarction Management

Abstract

Introduction: Myocardial infarction (MI) is the major cause of death worldwide. Nicotinamide-Adenine-Dinucleotide (NAD) is emerging as a metabolic target being a major coenzyme in mitochondrial oxidation and oxidative phosphorylation and a substrate of Sirtuins and PARPs, critical enzymes for cardiac remodeling. Altered NAD homeostasis is reported in several models of heart failure including MI with a striking upregulation of Nicotinamide-Riboside-Kinase2 (NMRK2) and a decrease of NAD levels. NMRK2 requires Nicotinamide Riboside (NR) as a substrate to produce NAD. In this study, we hypothesized that stimulating NMRK2 pathway by NR supplementation will upregulate NAD synthesis and subsequently improve metabolic state and cardiac function post-MI. Methods: MI was induced by the left anterior descending coronary artery ligation in 2-3 months old male mice. Echocardiography was performed at baseline, day 1, and day 4 following MI. At sacrifice, cardiac genes expression was evaluated by RT-qPCR and myocardial NAD levels were determined using a colorimetric assay. Histologically, Masson-Trichrome was performed on cardiac sections to assess cardiac fibrosis. Results: RT-qPCR analysis showed a 60 fold increase of Nmrk2 expression levels (P&it0.01) 4 days following MI. This upregulation was highlighted by the boost of NAD levels (708.81±79.83 pmoles/g of tissue in the MI-NR group vs 394.12 ±84.04 pmoles/g of tissue in the control group (p&it0.05)). Following MI, mitochondrial SIRT3 expression dropped by 40% and NR restored those levels which are critical for mitochondrial biogenesis. NR treatment markedly decreased the expression of PARP1 (1.22±0.34 in MI-NR group vs 2.69±0.45 in MI group (p&it0.05)), a well-known consumer of NAD. Histologically, fibrosis levels significantly dropped 4 days following NR treatment when compared to non-treated MI group (11±2,72 u.a vs 18±1,98 u.a, p&it0.05). Conclusion: NR treatment improves myocardial metabolic impairment, but not myocardial function, as early as 4 days following MI when compared to relative control groups. Additional experiments are underway to reveal the impact of NR treatment on cardiac remodeling and function at 7 days post-MI.