Intracellular NAMPT-NAD+-SIRT1 cascade improves post-ischaemic vascular repair by modulating Notch signalling in endothelial progenitors.

Wang P; Du H; Zhou CC; Song J; Liu X; Cao X; Mehta JL; Shi Y; Su DF; Miao CY

doi:10.1093/cvr/cvu220

Intracellular NAMPT-NAD+-SIRT1 cascade improves post-ischaemic vascular repair by modulating Notch signalling in endothelial progenitors.

Affiliations

1. Department of Pharmacology, Second Military Medical University, 325 Guo He Road, Shanghai 200433, China.
Authors
Wang P¹
Zhou CC¹
Song J¹
(3 authors)
2. 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.
Authors
Du H²
(1 author)
3. Institute of Immunology, Second Military Medical University, Shanghai, China.
Authors
Liu X³
Cao X³
(2 authors)
4. Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Authors
Mehta JL⁴
(1 author)
5. Zhongshan Hospital, Fudan University, Shanghai, China.
Authors
Shi Y⁵
(1 author)

Show all (6)

ORCIDs linked to this article

Cardiovascular Research, 23 Oct 2014, 104(3):477-488
https://doi.org/10.1093/cvr/cvu220 PMID: 25341895

The editors have expressed concern for this article. See Cardiovasc Res. 2021 Sep 28;117(11):2308.

This article has been corrected. See Cardiovasc Res. 2021 Sep 28;117(11):2308.

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.