Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways : novel insights into visfatin-induced angiogenesis
Adya, Raghu, Tan, Bee K., Punn, Anu, Chen, Jing and Randeva, Harpal S.. (2008) Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways : novel insights into visfatin-induced angiogenesis. Cardiovascular Research, Vol.78 (No.2). pp. 356-365. ISSN 0008-6363Full text not available from this repository.
Official URL: http://dx.doi.org/10.1093/cvr/cvm111
AIMS: Visfatin is a novel adipokine whose plasma concentrations are altered in obesity and obesity-related disorders; these states are associated with an increased incidence of cardiovascular disease. We therefore investigated the effect of visfatin on vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP-2, MMP-9) production and the potential signalling cascades.
METHODS AND RESULTS: In human umbilical vein endothelial cells (HUVECs), visfatin significantly and dose-dependently up-regulated gene expression and protein production of VEGF and MMPS and down-regulated expression of tissue inhibitors of MMPs (TIMP-1 and TIMP-2). The gelatinolytic activity of MMPs (analysed by zymography) correlated with mRNA and western blot findings. Interestingly, visfatin significantly up-regulated VEGF receptor 2 expression. Inhibition of VEGFR2 and VEGF [by soluble FMS-like tyrosine kinase-1 (sFlt1)] down-regulated visfatin-induced MMP induction. Visfatin induced dose-and time-dependent proliferation and capillary-like tube formation. Importantly, visfatin was noted to have anti-apoptotic effects. In HUVECs, visfatin dose-dependently activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt) and ERK1/2 (extracellular signal-regulated kinase) pathways. The functional effects and MMP/VEGF induction were shown to be dependent on the MAPK/PI3K-Akt/VEGF signalling pathways. Inhibition of PI3K/Akt and ERK1/2 pathways led to significant decrease of visfatin-induced MMP and VEGF production and activation, along with significant reduction in endothelial proliferation and capillary tube formation.
CONCLUSION: Our data provide the first evidence of visfatin-induced endothelial VEGF and AAMP production and activity. Further, we show for the first time the involvement of the MAPK and PI3K/Akt signalling pathways in mediating these actions, as welt as endothelial cell proliferation. Collectively, our findings provide novel insights into visfatin-induced endothelial angiogenesis.
|Item Type:||Journal Article|
|Subjects:||Q Science > QP Physiology
R Medicine > RC Internal medicine
|Divisions:||Faculty of Medicine > Warwick Medical School > Translational & Systems Medicine > Metabolic and Vascular Health
Faculty of Medicine > Warwick Medical School
|Library of Congress Subject Headings (LCSH):||Vascular endothelial growth factors, Metalloproteinases , Neovascularization, Cardiovascular system -- Diseases -- Research|
|Journal or Publication Title:||Cardiovascular Research|
|Publisher:||Oxford University Press|
|Official Date:||1 May 2008|
|Number of Pages:||10|
|Page Range:||pp. 356-365|
|Access rights to Published version:||Restricted or Subscription Access|
|Funder:||General Charities of the City of Coventry|
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