Pre-B cell colony enhancing factor (PBEF)/visfatin induces secretion of MCP-1 in human endothelial cells: role in visfatin-induced angiogenesis.
OBJECTIVE
Visfatin and Monocyte-Chemoattractant-Protein-1 (MCP-1) are elevated in cardiovascular pathologies, insulin-resistant and diabetic states. Visfatin has been reported to exhibit pro-angiogenic actions in human endothelial cells. Given MCP-1's well described pro-angiogenic properties we sought to study the potential interaction between visfatin and MCP-1 in human endothelial cells. We also explored the possible autocrine/paracrine mechanisms governing this potential interaction; specifically we looked at the effect of visfatin on MCP-1's putative receptor (CCR2 receptor) in human endothelial cells.


RESULTS
Using in vitro angiogenic assays (capillary tube formation and migration), Western blotting and RT-PCR, we found that visfatin, dose-dependently, induced MCP-1 as well as CCR2 levels. We also studied the involvement of PI3Kinase, MAPKinase and NF-kappaB pathways in visfatin induced MCP-1/CCR2 levels by employing LY294002, U0126 and BAY11-7085, respectively. We found the increase in MCP-1 and CCR2 levels by visfatin were negated by LY294002 and BAY11-7085, but not with U0126, suggesting the crucial role of PI3Kinase and NF-kappaB pathways in visfatin induced MCP-1 and its autocrine regulation via the CCR2 receptor. Finally, we consolidate the role of MCP-1 in visfatin-induced angiogenesis by employing CCR2 antagonist (RS-102895) and MCP-1 neutralising antibody, respectively.


CONCLUSIONS
Our novel data reveal that MCP-1 is pivotal in modulating visfatin-induced angiogenesis via NF-kappaB and PI3Kinase pathways. Furthermore, our findings elucidate the potential influence of autocrine/paracrine mechanisms (via the CCR2 receptor) underlying visfatin's angiogenic effects through MCP-1.
Adya
Raghu
R
Endocrinology & Metabolism Group, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry, UK.
Tan
Bee K
BK
Chen
Jing
J
Randeva
Harpal S
HS
D002070:Butadienes / Q000494:pharmacology; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013450:Sulfones / Q000494:pharmacology
C416282:BAY 11-7085; D002070:Butadienes; D018932:Chemokine CCL2; D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; D009025:Morpholines; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D019869:Phosphatidylinositol 3-Kinases