title: Oncostatin M-enhanced vascular endothelial growth factor expression in human vascular smooth muscle cells involves PI3K-, p38 MAPK-, Erk1/2- and STAT1/STAT3-dependent pathways and is attenuated by interferon-γ.
abstract: The pleiotropic cytokine oncostatin M (OSM), a member of the glycoprotein (gp)130 ligand family, plays a key role in inflammation and cardiovascular disease. As inflammation precedes and accompanies pathological angiogenesis, we investigated the effect of OSM and other gp130 ligands on vascular endothelial growth factor (VEGF) production in human vascular smooth muscle cells (SMC). Human coronary artery SMC (HCASMC) and human aortic SMC (HASMC) were treated with different gp130 ligands. VEGF protein was determined by ELISA. Specific mRNA was detected by RT-PCR. Western blotting was performed for signal transducers and activators of transcription1 (STAT1), STAT3, Akt and p38 mitogen-activated protein kinase (p38 MAPK). OSM mRNA and VEGF mRNA expression was analyzed in human carotid endaterectomy specimens from 15 patients. OSM increased VEGF production in both HCASMC and HASMC derived from different donors. OSM upregulated VEGF and OSM receptor-specific mRNA in these cells. STAT3 inhibitor WP1066, p38 MAPK inhibitors SB-202190 and BIRB 0796, extracellular signal-regulated kinase1/2 (Erk1/2) inhibitor U0126, and phosphatidylinositol 3-kinase (PI3K) inhibitors LY-294002 and PI-103 reduced OSM-induced VEGF synthesis. We found OSM expression in human atherosclerotic lesions where OSM mRNA correlated with VEGF mRNA expression. Interferon-γ (IFN-γ), but not IL-4 or IL-10, reduced OSM-induced VEGF production in vascular SMC. Our findings that OSM, which is present in human atherosclerotic lesions and correlates with VEGF expression, stimulates production of VEGF by human coronary artery and aortic SMC indicate that OSM could contribute to plaque angiogenesis and destabilization. IFN-γ reduced OSM-induced VEGF production by vascular SMC.
authors.affiliation: Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Demyanets
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaun
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rychli
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfaffenberger
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Kastl
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Hohensinner
authors.forename: Gersina
authors.initials: G
authors.lastname: Rega
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Katsaros
authors.forename: Taras
authors.initials: T
authors.lastname: Afonyushkin
authors.forename: Valery N
authors.initials: VN
authors.lastname: Bochkov
authors.forename: Matthias
authors.initials: M
authors.lastname: Paireder
authors.forename: Igor
authors.initials: I
authors.lastname: Huk
authors.forename: Gerald
authors.initials: G
authors.lastname: Maurer
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.forename: Johann
authors.initials: J
authors.lastname: Wojta
mesh_terms: D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D053683:Oncostatin M / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C508609:IL10 protein, human; C508598:IL4 protein, human; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D053683:Oncostatin M; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases