TY - JOUR
T1 - Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPAR gamma-Dependent Monocyte Differentiation and Function
AU - Bermudez, Beatriz
AU - Dahl, Tuva Borresdatter
AU - Medina, Indira
AU - Groeneweg, Mathijs
AU - Holm, Sverre
AU - Montserrat-de la Paz, Sergio
AU - Rousch, Mat
AU - Otten, Jeroen
AU - Herias, Veronica
AU - Varela, Lourdes M.
AU - Ranheim, Trine
AU - Yndestad, Arne
AU - Ortega-Gomez, Almudena
AU - Abia, Rocio
AU - Nagy, Laszlo
AU - Aukrust, Pal
AU - Muriana, Francisco J. G.
AU - Halvorsen, Bente
AU - Leonardus Biessen, Erik Anna
PY - 2017/6
Y1 - 2017/6
N2 - 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 (iNAMPT(hi)), 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 iNAMPT(hi) 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.. Finally, iNAMPT and peroxisome proliferator-activated receptor. showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator-activated receptor. 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. axis in atherosclerosis.
AB - 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 (iNAMPT(hi)), 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 iNAMPT(hi) 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.. Finally, iNAMPT and peroxisome proliferator-activated receptor. showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator-activated receptor. 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. axis in atherosclerosis.
KW - apoptosis
KW - atherosclerosis
KW - diet
KW - inflammation
KW - phenotype
KW - NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE
KW - INCREASED EXPRESSION
KW - IN-VIVO
KW - MACROPHAGES
KW - CELLS
KW - BIOSYNTHESIS
KW - PROLIFERATION
KW - ACTIVATION
KW - MICE
KW - INHIBITION
U2 - 10.1161/ATVBAHA.116.308187
DO - 10.1161/ATVBAHA.116.308187
M3 - Article
C2 - 28408371
SN - 1079-5642
VL - 37
SP - 1157
EP - 1167
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 6
ER -