FK866 compromises mitochondrial metabolism and adaptive stress responses in cultured cardiomyocytes

AimFK866 is an inhibitor of the NAD+ synthesis rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Using FK866 to target NAD+ synthesis has been proposed as a treatment for inflammatory diseases and cancer. However, use of FK866 may pose cardiovascular risks, as NAMPT expression is decreased in various cardiomyopathies, with low NAD+ levels playing an important role in cardiovascular disease progression. In addition, low NAD+ levels are associated with cardiovascular risk conditions such as aging, dyslipidemia, and type II diabetes mellitus. The aim of this work was to study the effects of FK866-induced NAD+ depletion on mitochondrial metabolism and adaptive stress responses in cardiomyocytes.Methods and resultsFK866 was used to deplete NAD+ levels in cultured rat cardiomyocytes. Cell viability, mitochondrial metabolism, and adaptive responses to insulin, norepinephrine, and H2O2 were assessed in cardiomyocytes. The drop in NAD+ induced by FK866 decreased mitochondrial metabolism without changing cell viability. Insulin-stimulated Akt phosphorylation, glucose uptake, and H2O2-survival were compromised by FK866. Glycolytic gene transcription was increased, whereas cardiomyocyte hypertrophy induced by norepinephrine was prevented. Restoring NAD+ levels via nicotinamide mononucleotide administration reestablished mitochondrial metabolism and adaptive stress responses.ConclusionThis work shows that FK866 compromises mitochondrial metabolism and the adaptive response of cardiomyocytes to norepinephrine, H2O2, and insulin.

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