Wang Pei, Xu Tian-Ying, Guan Yun-Feng, Su Ding-Feng, Fan Guo-Rong, Miao Chao-Yu
Department of Pharmacology, Second Military Medical University, 325 Guo He Road, Shanghai 200433, People's Republic of China.
Cardiovasc Res. 2009 Feb 1;81(2):370-80. doi: 10.1093/cvr/cvn288. Epub 2008 Oct 24.
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.
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.
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.
血管周围脂肪组织（PVAT）通过释放蛋白质因子抑制血管平滑肌细胞（VSMC）收缩并刺激VSMC增殖。本研究旨在确定内脂素是否参与PVAT的这些旁分泌作用，若参与，则探究其潜在机制。
与皮下和内脏脂肪组织相比，内脂素在Sprague-Dawley大鼠和猴主动脉PVAT中优先表达。通过内脂素特异性抗体/抑制剂以及重组内脂素的直接观察证明，PVAT衍生的内脂素是一种VSMC生长因子而非VSMC舒张因子。外源性内脂素通过细胞外信号调节激酶（ERK 1/2）和p38信号通路以剂量和时间依赖性方式刺激VSMC增殖。DNA合成增强和增殖标志物Ki-67上调进一步证实了这种增殖作用。内脂素对正常培养的VSMC没有抗凋亡作用，仅在H2O2诱导的细胞凋亡过程中发挥抗凋亡作用，排除了抗凋亡在内脂素诱导的VSMC增殖中的作用。胰岛素受体敲低对内脂素的作用没有影响。然而，内脂素作为烟酰胺磷酸核糖基转移酶生物合成烟酰胺单核苷酸（NMN），其介导的增殖信号通路和细胞增殖与内脂素的作用相似。
内脂素通过NMN介导的ERK1/2和p38信号刺激VSMC增殖。本研究提供了内脂素与PVAT旁分泌作用的分子联系，证明了内脂素在促进VSMC增殖方面的新功能，并揭示NMN是触发增殖过程的新信号分子。
