title: Visfatin exerts angiogenic effects on human umbilical vein endothelial cells through the mTOR signaling pathway.
abstract: The biologically active factors known as adipocytokines are secreted primarily by adipose tissues and can act as modulators of angiogenesis. Visfatin, an adipocytokine that has recently been reported to have angiogenic properties, is upregulated in diabetes, cancer, and inflammatory diseases. Because maintenance of an angiogenic balance is critically important in the management of these diseases, understanding the molecular mechanism by which visfatin promotes angiogenesis is very important. In this report, we describe our findings demonstrating that visfatin stimulates the mammalian target of the rapamycin (mTOR) pathway, which plays important roles in angiogenesis. Visfatin induced the expression of hypoxia-inducible factor 1α (HIF1α) and vascular endothelial growth factor (VEGF) in human endothelial cells. Inhibition of the mTOR pathway by rapamycin eliminated the angiogenic and proliferative effects of visfatin. The visfatin-induced increase in VEGF expression was also eliminated by RNA interference-mediated knockdown of the 70-kDa ribosomal protein S6 kinase (p70S6K), a downstream target of mTOR. Visfatin inactivated glycogen synthase kinase 3β (GSK3β) by phosphorylating it at Ser-9, leading to the nuclear translocation of β-catenin. Both rapamycin co-treatment and p70S6K knockdown inhibited visfatin-induced GSK3β phosphorylation at Ser-9 and nuclear translocation of β-catenin. Taken together, these results indicate that mTOR signaling is involved in visfatin-induced angiogenesis, and that this signaling leads to visfatin-induced VEGF expression and nuclear translocation of β-catenin. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
authors.affiliation: Division of Cardiovascular Diseases, Center for Biomedical Sciences, National Institute of Health, Nokbun-Dong, Eunpyung-Gu, Seoul 122-701, Republic of Korea.
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: So-Hee
authors.initials: SH
authors.lastname: Shin
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Mi Ran
authors.initials: MR
authors.lastname: Yun
authors.forename: Keon Jae
authors.initials: KJ
authors.lastname: Park
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Park
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D054409:Nicotinamide Phosphoribosyltransferase / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D054409:Nicotinamide Phosphoribosyltransferase; C546842:MTOR protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus