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Cardiovascular Research Advance Access originally published online on October 24, 2008
Cardiovascular Research 2009 81(2):370-380; doi:10.1093/cvr/cvn288
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Perivascular adipose tissue-derived visfatin is a vascular smooth muscle cell growth factor: role of nicotinamide mononucleotide

Pei Wang1, Tian-Ying Xu1, Yun-Feng Guan1, Ding-Feng Su1, Guo-Rong Fan2 and Chao-Yu Miao1,3,*

1 Department of Pharmacology, Second Military Medical University, 325 Guo He Road, Shanghai 200433, People’s Republic of China
2 Department of Pharmaceutical Analysis, Second Military Medical University, Shanghai 200433, People’s Republic of China
3 Shanghai Key Laboratory of Vascular Biology at Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai, People’s Republic of China

* Corresponding author. Tel: +86 21 25074374; fax: +86 21 65493951. E-mail address: chaoyumiao{at}yahoo.com.cn

Aims: Perivascular adipose tissue (PVAT) inhibits vascular smooth muscle cell (VSMC) contraction and stimulates VSMC proliferation by releasing protein factors. The present study was to determine whether visfatin is involved in these paracrine actions of PVAT, and if so, to explore the underlying mechanisms.

Methods and results: Visfatin was preferentially expressed in Sprague–Dawley rat and monkey aortic PVAT, compared with subcutaneous and visceral adipose tissues. The PVAT-derived visfatin was found to be a VSMC growth factor rather than a VSMC relaxing factor, which was proved by visfatin-specific antibody/inhibitor and direct observation of recombinant visfatin. Exogenous visfatin stimulated VSMC proliferation in a dose- and time-dependent manner via extracellular signal-regulated kinase (ERK 1/2) and p38 signalling pathways. This proliferative effect was further confirmed by enhancement of DNA synthesis and upregulation of proliferative marker Ki-67. Visfatin had no anti-apoptotic effect on normal cultured VSMCs, and it exerted an anti-apoptotic effect only during cell apoptosis induced by H2O2, excluding a role of anti-apoptosis in the visfatin-induced VSMC proliferation. Insulin receptor knockdown did not show any action on the visfatin effect. However, visfatin acted as a nicotinamide phosphoribosyltransferase to biosynthesize nicotinamide mononucleotide (NMN), which mediated proliferative signalling pathways and cell proliferation similar to the visfatin effect.

Conclusion: Visfatin stimulates VSMC proliferation via NMN-mediated ERK1/2 and p38 signalling. The present study provides a molecular link of visfatin to the paracrine action of PVAT, demonstrates a novel function of visfatin in promoting VSMC proliferation, and reveals NMN as a novel signalling molecule that triggers the proliferative process.

KEYWORDS Nicotinamide mononucleotide; Perivascular adipose tissue; Proliferation; Vascular smooth muscle cell; Visfatin

Time for primary review: 38 days


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