FK866 compromises mitochondrial metabolism and adaptive stress responses in cultured cardiomyocytes

Abstract

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.