Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function

Beatriz Bermudez, Tuva Borresdatter Dahl, Indira Medina, Mathijs Groeneweg, Sverre Holm, Sergio Montserrat-De La Paz, Mat Rousch, Jeroen Otten, Veronica Herias, Lourdes M. Varela, Trine Ranheim, Arne Yndestad, Almudena Ortega-Gomez, Rocio Abia, Laszlo Nagy, Pal Aukrust, Francisco J.G. Muriana, Bente Halvorsen, Erik Anna Leonardus Biessen

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objective-Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) mediates inflammatory and potentially proatherogenic effects, whereas the role of intracellular NAMPT (iNAMPT), the rate limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD)+ generation, in atherogenesis is largely unknown. Here we investigated the effects of iNAMPT overexpression in leukocytes on inflammation and atherosclerosis. Approach and Results-Low-density lipoprotein receptor-deficient mice with hematopoietic overexpression of human iNAMPT (iNAMPThi), on a western type diet, showed attenuated plaque burden with features of lesion stabilization. This anti-atherogenic effect was caused by improved resistance of macrophages to apoptosis by attenuated chemokine (C-C motif) receptor 2-dependent monocyte chemotaxis and by skewing macrophage polarization toward an anti-inflammatory M2 phenotype. The iNAMPThi phenotype was almost fully reversed by treatment with the NAMPT inhibitor FK866, indicating that iNAMPT catalytic activity is instrumental in the atheroprotection. Importantly, iNAMPT overexpression did not induce any increase in eNAMPT, and eNAMPT had no effect on chemokine (C-C motif) receptor 2 expression and promoted an inflammatory M1 phenotype in macrophages. The iNAMPT-mediated effects at least partly involved sirtuin 1-dependent molecular crosstalk of NAMPT and peroxisome proliferator-activated receptor γ. Finally, iNAMPT and peroxisome proliferator-activated receptor γ showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator-activated receptor γ pathway also in human carotid atherosclerosis. Conclusions-This study highlights the functional dichotomy of intracellular versus extracellular NAMPT, and unveils a critical role for the iNAMPT-peroxisome proliferator-activated receptor γ axis in atherosclerosis.

Original languageEnglish
Pages (from-to)1157-1167
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume37
Issue number6
DOIs
Publication statusPublished - Jun 1 2017

Keywords

  • apoptosis
  • atherosclerosis
  • diet
  • inflammation
  • phenotype

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Bermudez, B., Dahl, T. B., Medina, I., Groeneweg, M., Holm, S., Montserrat-De La Paz, S., Rousch, M., Otten, J., Herias, V., Varela, L. M., Ranheim, T., Yndestad, A., Ortega-Gomez, A., Abia, R., Nagy, L., Aukrust, P., Muriana, F. J. G., Halvorsen, B., & Biessen, E. A. L. (2017). Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function. Arteriosclerosis, thrombosis, and vascular biology, 37(6), 1157-1167. https://doi.org/10.1161/ATVBAHA.116.308187