Abstract 20541: Nicotinamide Phosphoribosyltransferase (NAMPT) Modulates Oxidative Stress via Nrf2: Roles of Intracellular and Extracellular NAMPT
We previously identified the nicotinamide phosphoribosyltransferase (NAMPT, also known as pre-B cell colony enhancing factor or PBEF), as a candidate gene promoting both acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI) with circulating extracellular NAMPT (eNAMPT) potently inducing NFkB signaling in lung endothelium. We also confirmed the intracellular NAMPT (iNAMPT) enzymatic activity is strongly associated with apoptosis inhibition in neutrophils, which prolongs the half-life of infiltrated neutrophil, to exacerbate acute lung inflammation. In this study, we further characterize the novel function of NAMPT via oxidative stress modulation through Nrf2, which is a key regulator in cellular adaptive response to pro-inflammatory oxidative stimulation. Direct exposure to eNAMPT activates Nrf2, and its down-stream signaling, by upregulation of cellular Nrf2 protein levels. In addition, eNAMPT promotes NAMPT expression, in a positive feedback loop to increase both iNAMPT and eNAMPT, presumably via Nrf2 dependent oxidative stress transcriptional pathways. However, NAMPT protein expression is increased by Nrf2 knockdown (by specific siRNA) in human pulmonary endothelial cells or in lung tissue of Nrf2 knockout mice, which suggests that NAMPT expression is regulated by Nrf2, via non-classic transcriptional pathways. Interestingly, over-expressed iNAMPT directly binds to Nrf2, thereby inhibiting its transcriptional activity; in addition, over-expressed iNAMPT binds and inhibits Keap1, which leads to accumulation of Nrf2 in the cytosol. These novel findings characterize the complex modification of intracellular adaptive response to oxidative stress via Nrf2, by extracellular NAMPT, as well as intracellular NAMPT. These studies provide new molecular mechanisms of NAMPT-mediated acute lung inflammation and oxidative stress modulation.
Author Disclosures: T. Jiang: None. T. Wang: None. L. Hecker: None. D.D. Zhang: None. J.G. Garcia: None.
- © 2014 by American Heart Association, Inc.