[R01] NNMT Inhibition for treating heart failure
Ente: National Heart Lung and Blood Institute
Scadenza: 2029-05-31
Importo max: $707,281
Paese: US
Descrizione
Project Summary
Heart failure (HF), spanning from HF with preserved ejection fraction (HFpEF) to HF with reduced ejection
fraction (HFrEF), is a leading cause of death worldwide, and among Americans, accounts for 14% of deaths at
present. Various pathophysiologic stresses have been clinically and experimentally identified to contribute to
HF via distinct molecular mechanisms. However, our limited understanding of the pathogenesis of HF and the
poor prognosis of HF strongly underscores the need for further mechanistic investigation and additional
therapeutic strategies. Many studies have identified NAD+ deficiency as a central defect in HF of various
etiologies. NAD+ deficiency has been attributed to decreased NAD+ salvage resulting from impaired expression
of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway,
recycling nicotinamide (NAM) back into NAD+. Our recent studies and preliminary data establish a novel
mechanism underlying NAD+ deficiency in failing hearts, namely catabolism of NAM to methyl-
nicotinamide (1-MNA) via induction of the enzyme, Nicotinamide N-Methyltransferase (NNMT). NNMT is
induced in multiple murine models of HFrEF secondary to hemodynamic stress or genetic defects in
autophagy. NNMT is also induced in a murine model of HFpEF and in end-stage failing human hearts. These
observations form the basis of our central hypothesis, that NNMT induction results in NAD+ deficiency,
in HFpEF and HFrEF and NNMT inhibition could be harnessed to prevent or treat HF. To test these
hypotheses and to rigorously evaluate the feasibility of this novel therapeutic approach, we present two aims.
Aim 1 will determine if NNMT induction is central to the pathophysiology of HFpEF and HFrEF. By evaluating
NAD+ metabolites, NAD+ flux, and the progression of HF, we will determine if NAD+ deficiency attributable to
increased NAM catabolism via NNMT induction is a conserved molecular event in HFrEF and HFpEF and
determine the contribution of this pathway in modulating existing strategies based on administering NAD+ pool
precursors for preventing or treating HF. Aim 2 will determine if genetic or pharmacological inhibition of NNMT
will prevent or reverse HFrEF and HFpEF. By genetically deleting or pharmacologically inhibiting NNMT, we
will determine the relevance of NNMT induction in the development of HFrEF or HFpEF, and identify molecular
mechanisms by which 1-MNA could contribute to HF. The successful completion of these two aims will identify
NNMT as a central mechanism underlying the development of HFpEF and HFrEF. Successful completion of
this project will provide insight into the pathophysiology of HF and provide pre-clinical evidence for NNMT as a
potential target for the prevention and treatment of HF.
Istituzione: UNIVERSITY OF CALIFORNIA LOS ANGELES
PI: E Dale Abel
Progetto: 5R01HL180429-02
Settori: National Heart Lung and Blood Institute
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