Abstract 16790: Hematopoietic Nampt Overexpression Impairs Monocytic Differentiation and Polarization Towards Ccr2high Phenotype, pPeventing Atherosclerosis Progression
Visfatin is a ubiquitously expressed enzyme originally viewed as a proinflammatory adipokine, the recent notion that it is identical to NAMPT, a key molecule in the salvage pathway of the NAD+/NADH biosynthesis, has considerably widened its physiological impact. As NAMPT serum levels were recently shown to be elevated in patients with unstable angina pectoris. Herein, we have examined the potential pathogenic role of NAMPT in atherosclerosis in vivo and in vitro. LDLr−/− chimeras were generated with lentiviral NAMPT overexpression in the hematopoietic lineage and effects were determined on leukocyte differentiation and activation as well as on plaque development. In keeping with its presumed anti-apoptotic effect, neutrophils and macrophages from mice with superphysiological NAMPT expression (+43%; P<0.01) were less apoptotic compared to the control group (−40 % and −15% respectively; p<0.05). Moreover NAMPT overexpression appeared to sensitize myeloid precursors not only to G-CSF (+52%; p= 0.009), but also to GM-CSF (+34%; p= 0.03). Remarkably, the number of circulating granulocytes LY6Ghigh was unchanged by NAMPT overexpression, while CD11b+ monocyte numbers were even reduced (−51%; p=0,036). Monocytes of mice with NAMPT overexpression were polarized towards a Ly6Clow phenotype and showed decreased CCR2 expression (−39.8%; p=0.02). Despite these profound effects, total intima area and plaque cellularity were unchanged upon NAMPT overexpression, while plaque collagen content did not differ between groups as well. However, reconstitution with NAMPT overexpressing bone marrow resulted in a sharp reduction in necrotic core size (−46%; P=0.0001, n=10) and in plaque apoptosis (−56%; P<0.001) compared to the control, while plaque macrophage content was also significantly reduced (−60%, p= 0.0002, n=10), consistent with the aforementioned anti-apoptotic and monocytopenic activity of NAMPT. In conclusion, we are the first to demonstrate profound phenotypic effects of hematopoietic NAMPT overexpression on monocytic differentiation, survival and atherosclerosis, identifying this longevity gene as a promising target for therapeutic intervention in inflammation related disorders such as atherosclerosis
- © 2010 by American Heart Association, Inc.