Intracellular NAMPT‚ÄìNAD+‚ÄìSIRT1 cascade improves post-ischaemic vascular repair by modulating Notch signalling in endothelial progenitors
Authors: Jie Song
Yi Shi
Can-Can Zhou
Ding-Feng Su
Pei Wang
Xingguang Liu
Chao-Yu Miao
Xuetao Cao
Jawahar L Mehta
Hui Du
Journal: Cardiovascular Research (2014)
Discipline: CLINICAL MEDICINE
Keywords: Endothelial progenitor cells; Ischaemia; NAMPT; Neovascularization; Visfatin.
Affiliations: Department of Pharmacology, Second Military Medical University, 325 Guo He Road, Shanghai 200433, China., Department of Pharmacology, Second Military Medical University, 325 Guo He Road, Shanghai 200433, China Department of Pharmacy, General Hospital of Lanzhou Military Region, Lanzhou, China., Institute of Immunology, Second Military Medical University, Shanghai, China., Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA., Zhongshan Hospital, Fudan University, Shanghai, China., Department of Pharmacology, Second Military Medical University, 325 Guo He Road, Shanghai 200433, China  .

Abstract:  Aims: Intracellular nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis. This study investigated the role of NAMPT-mediated NAD(+) signalling in post-ischaemic vascular repair. Methods and results: Mouse hind-limb ischaemia up-regulated NAMPT expression and NAD(+) level in bone marrow (BM). Pharmacological inhibition of NAMPT by a chemical inhibitor FK866 impaired the mobilization of endothelial progenitor cells (EPCs) from BM upon ischaemic stress. Transgenic mice overexpressing NAMPT (Tg mice), but not H247A-mutant dominant-negative NAMPT (DN-Tg mice), exhibited enhanced capillary density, increased number of proliferating endothelial cells, improved blood flow recovery, and augmented collateral arterioles in the ischaemic limb. In cultured BM-derived EPCs, inhibition of NAMPT suppressed proliferation, migration, and tube formation, whereas overexpression of NAMPT induced opposite effects. The promoting effects of NAMPT on EPCs were abolished by silencing of sirtuin 1 (SIRT1), rather than silencing of SIRT2-7. Overexpression of NAMPT led to a SIRT1-depedent enhancement of Notch-1 intracellular domain deacetylation, which inhibited Delta-like ligand-4 (DLL4)-Notch signalling and thereby up-regulated of VEGFR-2 and VEGFR-3. Injection of recombinant VEGF induced a more pronounced EPC mobilization in Tg, but not in DN-Tg, mice. Furthermore, overexpression of NAMPT down-regulated Fringe family glycosyltransferases in a SIRT1-dependent manner, which rendered Notch more sensitive to the pro-angiogenic ligand Jagged1 rather than the anti-angiogenic ligand DLL4. Conclusions: These results demonstrate that intracellular NAMPT-NAD(+)-SIRT1 cascade improves post-ischaemic neovascularization. The modulation of Notch signalling may contribute to the enhanced post-ischaemic neovascularization. 

Retracted: No

PubPeer comments:
 Figure 2G has unexpected repeating groups of events in both Tg panels. Could the authors please check what happened here?  , 
 Figure 4C shows two panels that are not labeled, so it is not sure if these are supposed to show the same experiment. However, the bottom panel appears to contain some repetitive features. Could the authors please comment?  , 
 #1 There is a little bit going on in the DN-Tg panel of 2H.  There is a lot going on in the Tg panel, so I have paired it with a rotated version of itself, in the hope that the relationships of the repeated constellations will be clearer.  , 
 #1 The Tg panel of 2G has one more constellation repetition - another rotated version.  , 
 2020 Expression of concern. https: academic.oup.com cardiovascres advance-article-abstract doi 10.1093 cvr cvaa248 5895172?redirectedFrom=fulltext The Editoru2019s attention was drawn to this paper by a reader regarding concerns around Figure 2G H and Figure 4C. The Editorial Office received an erratum request from the first author of the paper, Dr Pei Wang, afterwards. The authors have admitted error and have requested the above-mentioned figures be corrected, as well as Figure 5D, alongside an explanation. This is being reviewed by Editors and the ESC family Journal Ethics committee. The Editors of Cardiovascular Research have decided to place an expression of concern related to this paper... , 
 Looks to be different exposures of the same bands.  , 
 http: www.most.gov.cn tztg 202101 t20210121_160971.htm  ,